Functional dyspepsia (FD) is a common functional gastrointestinal disease which bears a significant burden on society and individuals. Despite the high prevalence of FD, its pathophysiology remains poorly understood and the treatment options are limited and unsatisfactory. In the absence of effective pharmacological treatments for FD, non-pharmacological approaches, including: reassurance, lifestyle modification, psychotherapy, dietary interventions, medical food, acupuncture, and electrical stimulation and modulation are sought after by many physicians and FD patients. In this article, we review clinical studies which investigate non-pharmacological therapies for FD. We will also discuss potential mechanisms involved in the therapeutic effects of these non-pharmacological approaches. Though the evidences to support the routine use of the non-pharmacological management is still lacking, the non-invasive nature and potentially minimal side-effects of these therapies may be attractive in the FD management. In order to confirm the clinical effectiveness of these non-pharmacological approaches, more well-conducted, methodologically rigorous, and large-scaled clinical trials are required.
Functional dyspepsia (FD) refers to a group of symptoms arising from the epigastric region that do not originate from an organic disease.1 FD is divided into 2 diagnostic categories of meal-related dyspeptic symptoms in the Rome IV criteria; they include: post-prandial distress syndrome (PDS), characterized by postprandial fullness and early satiation, and epigastric pain syndrome (EPS), characterized by epigastric pain and burning.2 The prevalence of FD in Asia ranges from 8% to 23%.3 Though it is not a life-threatening disease, it significantly impairs patients’ quality of life and bears a significant economic burden on society and individuals.4 Despite its high prevalence and disease burden, the pathophysiology of FD remains poorly understood. However, several mechanisms have been proposed, including: impaired gastric accommodation,5 delayed gastric emptying,6 visceral hypersensitivity,7
We performed a systematic approach in the collection and review of relevant literature. PubMed was searched from 1994 through to December 2018 with a combination of the following basic and MeSH (medical subject headings) terms: “functional dyspepsia” or “functional gastrointestinal disorder” as the population; “medical food,” “acupuncture,” “psychotherapy,” “electrical stimulation” or “non-pharmacological” as the intervention; “placebo” or “control” as the comparison; and “placebo controlled” or “randomized” as the study design. Reference lists of included studies were then manually searched for relevant studies.
A number of clinical trials have shown that patients with functional bowel disorders (eg, FD, irritable bowel syndrome [IBS], etc) benefit from a greater placebo response when compared to patients with organic gastrointestinal diseases.20 One meta-analysis including 45 FD trials showed a placebo response rate of 31% to 45%.21 A 2006 Cochrane review found an average 56% placebo response among FD patients.22 The underlying mechanisms behind the high placebo response rate among FD patients are still unclear, however, no studies have found a significant difference in the personality traits between placebo responders and non-responders. To date, the only factors predictive of a lower placebo response rate are a body mass index of lesser than 25 and a consistent predominant symptom pattern.20 Talley et al20 suggested that the placebo response to treatment can be maximized by a firm diagnosis that must be followed by explanation and reassurance. In daily practice, clinicians may take advantage of the placebo effect by reassuring the FD patient by explaining the pathophysiology of FD and the unlikelihood of cancer in order to relieve patients’ anxiety and lead to symptomatic improvement.
Lifestyle factors are linked with the development of dyspeptic symptoms. For example, life stress, anxiety, and the use of inadequate coping strategies are predictors of FD.23 Furthermore, anxiety was associated with PDS, but not with the EPS in a Swedish population study.24 A Taiwanese FD study showed that PDS was independently associated with dimensions of somatization, depression, and phobia.25 In addition, we and Miwa et al26 both found that FD patients have a higher prevalence of sleep difficulties.4 A large United States-based community study demonstrated that difficulty falling asleep is an independent risk factor for dyspepsia.27 Though the studies evaluating the beneficial effect of adjustments in lifestyle are lacking, measurements to improve lifestyle may relieve dyspeptic symptoms. FD patients with refractory and persistent symptoms after conventional treatment may attempt lifestyle modification.
Numerous studies have evaluated psychological therapy in the treatment of IBS,28 however, the body of evidence in support of psychological therapies for FD is rather limited. Nonetheless, patients who suffer from psychiatric comorbidities or who are otherwise non-responsive to pharmacological interventions may be suitable candidates for psychological therapy. Various methods of psychotherapy in the treatment of FD have been evaluated, including hypnotherapy,29 cognitive behavioral therapy,30–34 and psychoanalytic psychotherapy,35,36 as summarized in Table 1. The American College of Gastroenterologists and the Canadian Association of Gastroenterologists recently reviewed psychotherapy among other interventions in the treatment of FD. Each of the 12 trials reviewed indicated a significant benefit from psychological therapies compared to control (relative risk [RR], 0.53; 95% confidence interval [CI], 0.44–0.65) with a number needed to treat of 3. Despite these positive results, the reviewers stated that the evidential basis for psychotherapy in the treatment of FD is weak. This is because the research to date has been far too heterogeneous—both in terms of the study populations and type of psychotherapeutic intervention—for any definitive support favoring the use of psychotherapy in the treatment of FD.37 It can be difficult to judge the therapeutic effect objectively due to the heterogeneity in psychological treatment methods. The studied patients also ranged in their duration of illness and varied in the symptoms of FD that they had reported. The included studies also lacked methodological rigor; the study interventions were neither blinded nor were various interventions directly compared with each other. In addition, unlike the current standards for pharmaceutical drug trials, the lack of a placebo arm in the clinical trials involving psychotherapy also weakens the evidence for such therapy. Furthermore, the use of psychotherapy in FD patients is lessened by a lack of familiarity among gastroenterologists with such interventions, as well as patients who do not recognize or are unwilling to accept the influence of psychological symptoms on the severity of gastrointestinal symptoms. Future studies should address these limitations in order to convince patients and healthcare providers to introduce psychotherapy for the treatment of FD.
Starting from the Rome III consensus, FD, and in particular PDS, has been considered a disorder related to food ingestion.38 Avoiding foods which trigger indigestion may be of benefit. Several studies and systemic reviews have indicated that wheat-containing foods, fatty or spicy foods, and carbonated drinks can trigger dyspeptic symptoms,39 as summarized in Table 2. However, it is not yet understood exactly how these foods trigger FD symptoms.
Another dietary intervention for the treatment of FD is medical food; defined by the United States Food and Drug Administration as foods which are formulated to be consumed or administered enterally under the supervision of a physician which is intended for the specific dietary management of a disease or condition.40,41 Medical foods, unlike food supplements, require safety reviews by panels of toxicologists and must be generally recognized as safe for consumption, although phase 1, 2, and 3 trials are not required.42 Medical foods can affect several pathophysiological mechanisms in FGIDs, such as functioning as an anti-inflammatory, causing smooth muscle relaxation, analgesia, mitigation of gut barrier dysfunction, and stimulation or inhibition of gastrointestinal receptors.41 Several medical foods are available in Europe and United States for the treatment of FD. In Western countries, caraway oil (CO) has often been combined with peppermint oil (PO) in order to treat abdominal discomfort and pain. Two randomized controlled trials have demonstrated that this PO + CO combination improves FD patients’ global symptom impressions in a manner comparable with cisapride43 and superior to placebo.44 A separate randomized controlled trial (RCT) compared the efficacy of CO + L-menthol (FDgard) or a placebo as adjuvants to conventional medications in the treatment of FD. After 4 weeks of treatment, the CO + L-menthol group showed improved clinical global impressions to a greater extent than placebo (61.2% vs 48.9%, respectively), however, the difference was not statistically significant. CO is thought to produce its therapeutic effect through a prokinetic effect whereas PO produces its therapeutic effect via kappa-opioid-receptor dependent anti-nociception, anti-inflammatory properties, and TRPM8-receptor dependent smooth muscle relaxation.41
Another medical food of interest is STW 5—an herb composed of garden angelic root, milk thistle fruits, greater celandine, bitter candy tuft, caraway fruits, liquorice root, chamomile flowers, balm leaves, and peppermint leaves. STW 5 has been used to treat a variety of functional digestive symptoms.45 In a meta-analysis of 3 RCTs evaluating STW 5 in the treatment of FD, Melzer et al46 found treatment with STW 5 (n = 138) to be more effective than placebo (n = 135) with regard to the severity of the most bothersome gastrointestinal symptom (
Another non-pharmacological avenue for the treatment of FD is probiotics. Probiotics are living microorganisms that (when consumed) have the potential to confer a beneficial health effect; they can be marketed as a medical food.51 Probiotics containing
Medical foods may appeal to those who have failed conventional therapies or who are seeking dietary management for their FD symptoms. Table 3 displays trials investigating medical food to treat FD. What is considered medical food varies between regions. Till now, there has not been enough evidence to warrant the clinical use of medical foods. Future large, well-controlled studies are needed to assess both the safety and efficacy of medical foods in the treatment of FD patients with different races and ethnicities.
Acupuncture has been increasingly used as a non-pharmacological treatment of FD. Traditionally, acupuncture involves the stimulation of acupuncture points by penetration of the skin with solid metallic needles, followed by manual manipulation of the needle (ie, twisting, lifting, and thrusting). Acupuncture points can also be stimulated through electro-acupuncture, passing electrical currents through an inserted needle to stimulate a specific acupuncture point at a certain frequency and intensity. Unlike traditional acupuncture, electro-acupuncture provides a more objective, quantifiable method of acupuncture.57 Two meta-analyses have evaluated the efficacy and safety of acupuncture to treat FD patients. The analysis by Kim et al58 included 20 RCTs and a total of 1423 FD patients who received either acupuncture or another therapy (meta-analysis 1). The second analysis by Zhou and colleagues59 included 24 RCTs and a total of 3097 FD patients receiving either acupuncture or electroacupuncture therapy (meta-analysis 2). Both meta-analyses showed that acupuncture was more beneficial than sham (meta-analysis 1: RR, 2.66; 95% CI, 1.85–3.22; meta-analysis 2: RR, 2.03; 95% CI, 1.55–2.67) and with usual pharmacological medications (meta-analysis 1: RR, 1.18; 95% CI, 1.09–1.27; meta-analysis 2: RR, 1.10; 95% CI, 1.04–1.17). Both meta-analyses also demonstrated that acupuncture enhanced the therapeutic benefit of FD medications (meta-analysis 1: RR, 1.23; 95% CI, 1.02–1.48; meta-analysis 2: RR, 1.24; 95% CI, 1.16–1.33).
In order to better understand acupuncture’s therapeutic mechanism, a recent study used functional brain imaging (positron emission scan) in FD patients to evaluate the response in brain activity to acupuncture treatment. Acupuncture treatment resulted in a decrease in FD symptom scores that correlated with an extensive deactivation of cerebral activity in the brainstem, anterior cingulate cortex, insula, thalamus, and hypothalamus.60 This finding suggests that acupuncture’s therapeutic mechanism may involve modulation of the homeostatic afferent processing network.
While these studies show a beneficial effect on FD symptoms, there are several limitations. The two meta-analyses included studies mostly from Eastern countries, namely China. Secondly, there has not yet been a multicenter, large-scale RCT for acupuncture in the treatment of FD. Furthermore, in many studies included in the meta-analysis, the definition of FD varied widely. FD can be based on Rome I, II, or III criteria or just vague dyspeptic symptoms not defined by Rome, and the outcomes after acupuncture were evaluated either dichotomously or continuously. Thus, the final results may be biased. Thirdly, most studies have had a short (if any) duration of follow-up. Fourthly, studies to date have lacked a standardized method of symptom evaluation, such as the Nepean Dyspepsia Index. Finally, most studies used fixed acupuncture points, such as Stomach-36 (ST36) and Pericardium-6 (PC6) as opposed to the traditional approach of selecting acupuncture points based off of each individual’s symptoms. Given these limitations, a recent Cochrane review stated that “It remains unknown whether manual acupuncture or electro-acupuncture is more effective or safer than other treatments” in FD patients.61 Future large-scaled, multinational, and methodologically rigorous clinical trials are needed to confirm the effectiveness of acupuncture in treating FD patients.
Transcutaneous electrical stimulation of acupuncture points, also known as transcutaneous electrical acustimulation (TEA), is a recent variant of electro-acupuncture that has been used in the treatment of FD (Table 4).62 TEA uses electrodes placed on the skin’s surface for electrical stimulation. Having electrodes on the skin’s surface reduces the depth of penetration of the electrical current. Compared to electro-acupuncture and conventional acupuncture, TEA is less invasive, can be self-administered by the patient, and can be conducted more frequently. Two trials have evaluated the efficacy of TEA in the treatment of FD. In a crossover study of FD patients, Ji et al63 conducted TEA at acupuncture points ST36 and PC6 for 2 weeks followed by 2 weeks of transcutaneous electrical stimulation at sham acupuncture points, or vice versa (Figure). They found TEA was superior to sham in decreasing dyspeptic symptom scores, gastric emptying, and gastric accommodation.63 A pilot study investigated the fasting and postprandial effects of TEA at ST36 and PC6 vs sham on gastric motility and accommodation in FD patients and healthy controls. They found that verum TEA significantly increased gastric accommodation in FD patients only, and increased the percentage and power of postprandial gastric slow waves as well as vagal activity in FD patients.64 These results suggest that self-administrated TEA can improve gastric motility and symptom relief for FD patients.
In a study by Köklü et al,65 transcutaneous electrical stimulation was conducted via vacuum interferential current therapy. Therapy was superior to placebo in improving epigastric discomfort, pyrosis, bloating, early satiation, and postprandial fullness in FD patients.65 The location of electrical stimulation in this study corresponded to 4 acupuncture points: Bladder 18–21.67
Vagus nerve stimulation has demonstrated anti-nociceptive effects on various types of pain.68–70 A recent study showed an impressive analgesic effect using percutaneous electric nerve field stimulation (PENFS) in the external ear to treat patients with functional abdominal pain (including FD patients).66 One hundred and 4 adolescents (aged 11–18 years) with chronic functional abdominal pain were enrolled. Fifty-seven received PENFS with 3.2 volts in rectangular pulse wave and alternating frequencies (1 msec pulses of 1 Hz and 10 Hz) every 2 seconds, while the remaining 47 patients received sham stimulation. Patients in the PENFS group had a lower “worst pain score” than with sham group after 3 weeks of treatment (5 vs 7,
Non-pharmacological therapies including reassurance, lifestyle modification, psychotherapy, dietary management, medical food, acupuncture, and electrical stimulation/modulation can be useful options for the treatment of FD (Table 5). Non-pharmacological therapies for FD are increasingly being sought by families and medical providers for treating dyspeptic symptoms. The non-invasive nature and potentially minimal side-effects of these non-addictive, non-pharmacological therapy are likely to benefit FD patients, especially those who have failed conventional therapies. The current evidence to warrant the routine use of non-pharmacological therapies in treating FD patients remains limited, though some FD patients do respond well to non-pharmacological management. The timing to incorporate non-pharmacological therapy into the standard therapy and its position in the current treatment algorithm for FD patients remains to be settled. It is still unclear whether it should be used for refractory FD patients or used as an adjunct to the pharmacological therapy. More well-conducted and large-scaled clinical trials are required to confirm their effectiveness and to identify possible adverse effects in FD treatment.