Introduction

Gastroparesis (GP) is a complicated and multi-factorial disorder associated with variable symptoms of nausea, vomiting, early satiety, upper abdominal pain, post-prandial fullness, bloating, and/or belching . Although these symptoms may be associated with chronic diseases such as diabetes, Parkinson’s, and collagen vascular diseases, as well as certain medications (i.e., narcotics, muscarinic cholinergic antagonists, tricyclic antidepressants ), and surgery (i.e. fundoplication leading to vagus nerve injury), the majority of GP cases are idiopathic. Approximately half of patients diagnosed will have no detectable underlying abnormality.

Pharmacologic intervention alone may not provide sufficient symptom relief. The complex interactions between the brain, central nervous system, and the enteric nervous system are intriguing, and offer an opportunity to study novel approaches that improve the well-being of affected individuals. This chapter reviews the efficacy and mechanisms of therapies that have been classified as “complementary” or “alternative” for gastroparesis and its symptoms.

Acupuncture

Acupuncture has been an important part of Traditional Chinese Medicine (TCM) for more than 2500 years. Acupuncture is performed by inserting into the skin very fine acupuncture needles to manipulate the flow of Qi (Chi) in the body, which is the life force energy that is present in all living bodies. The principles of Traditional Chinese Medicine (TCM), which differ from what conventional medicine teaches, hold that symptoms and illnesses result from the disruption of energy flow along channels in the body, called meridians . For instance, if there is a blockage or excess of energy (Stagnant Qi) in a meridian, the individual may have symptoms of pain, inflammation, headache, high blood pressure, depression, or menstrual problems. If there is not enough energy within an organ to perform its function and duties (Deficient Qi), as with “spleen Qi deficiency”, the individual may easily to have symptoms of chronic diarrhea and fatigue. Meridians are often named according to major internal body organs, even though the location of the meridians or the sites of specific acupuncture points may not necessarily align with the actual anatomic positions of the named body organs, adding confusion about the terminology for those who are new to the field. Acupuncture points, where Qi gathers in the body, are found along the meridians. There are 365 acupuncture points along 12 main meridians, in addition to numerous extra acupuncture points located elsewhere on the body.

What is important to know when evaluating studies using acupuncture is that stimulating energy flow can be achieved using different techniques, often involving needles, but sometimes by applying pressure at key points alone. The most familiar type of acupuncture, as has been discussed, is transcutaneous acupuncture (TA) in which needles, sometimes the diameter of a human hair, are gently inserted at specific acupuncture points.

Once the needles are inserted, the trained practitioner may rapidly rotate the needles (twirling), or, move them in and out rapidly (lifting – thrusting) and leave the needles in place for a specific duration of time to generate a desired response. Transcutaneous electroacupuncture (TEA) involves passing a gentle electrical current between pairs of inserted acupuncture needles. The electrical current augments the effects created by the needle insertion and manipulation. There are other ways to administer acupuncture, but most of the studies done for gastroparesis or its symptoms involve either TA or TEA. Acupuncture is typically administered in multiple sessions, as there is not always an immediate or sustained effect with one session alone. In clinical practice, practitioners trained in all the modalities of TCM, including herbal medicine and Qi Gong, may not use acupuncture as a modality in isolation. However, in most integrative medicine centers, in keeping with the conventional medicine view that single therapy is generally preferable than combination therapy, acupuncture frequently is encountered alone, devoid of other TCM modalities. Similarly, most research studies trying to evaluate the impact of acupuncture will study it separately from any other TCM modalities that might confound interpretation of the study results.

According to the principles of TCM, the management of symptoms related to gastroparesis are attributed to the stagnation of energy flow through the spleen meridian. Commonly used acupuncture points for the treatment of gastrointestinal symptoms are: Zhongwhan (CV 12), which is thought to resolve stomach “fullness or stuffiness”; Zusanli (ST 36) to increase gastrointestinal motility by increasing Qi, and Neiguan (PC 6), which regulates Qi and can bring comfort to the chest. Other points used for the treatment of symptoms related to gastroparesis include Liangmen (ST21) and Sanyinjiao (SP6). Thus, with the proper placement and insertion of needles for defined periods of time and frequency that stagnant Qi can be dispersed, and deficient Qi boosted (tonified) as a result of manipulating the flow of Qi on the involved meridians and organs.

Humans have used acupuncture for thousands of years with minimal few side effects so it is no wonder that acupuncture remains an attractive option today for symptomatic patients with gastroparesis. Many conventionally trained clinicians question the efficacy of acupuncture because of a lack of familiarity with TCM terminology and difficulty reconciling its principles with those of Western medicine. There are also legitimate questions about its mechanisms of action, and concerns about what constitutes an appropriate control in acupuncture studies. A “sham” acupuncture procedure – often used as a control- depending on how it is defined, may not be without physiologic effects. Nevertheless, how acupuncture exerts its effects is a subject of tremendous curiosity and study. Some argue that acupuncture administered at key acupoints has an antinociceptive effect on visceral pain by restraining spinal dorsal horn neuron activation by noxious stimuli . An effect on neural reflexes has been postulated from the observation that gastric motility, induced by acupuncture at ST36, is diminished by vagotomy and increased by sympathectomy . A central effect has been suggested as well by functional MRI (fMRI) demonstrating that acupuncture at specific points, like ST 36, activates areas in the brain associated with the somatosensory system and emotional regulation . These observations suggest that acupuncture might have more than one mechanism of action, just as other pharmacologic therapies used today for the treatment of functional GI disorders. understanding the scientific basis for the efficacy of acupuncture through ongoing research is critical if this therapy is to gain more traction for GP, a disorder that currently has no cure.

Animal studies have provided the most insight into the mechanisms by which acupuncture exerts its effect on gastric motility. Several studies done by different groups of investigators showed that TEA at ST 36, or auricular acupuncture in normal rats, improved gastric dysrhythmias by increasing gastric slow waves . A similar effect has been observed in rats with streptozocin-induced diabetic gastroparesis or burn-induced gastroparesis who received TEA or auricular acupuncture . Some studies have suggested that the effects of acupuncture are mediated through the expression of ghrelin, an endogenous growth hormone secretagogue receptor ligand with prokinetic effects, locally in the gastric antrum or in the central nervous system . Other studies suggest that the c-kit ligand pathway is involved. Among the most interesting studies are those examining improved gastric emptying in diabetic rats with TEA, which was accompanied by a proliferation and restoration of a cellular network of Interstitial Cells of Cajal . Less information about the effect of TA on gastric function exists for humans. However, transcutaneous electroacupuncture (TEA) in healthy volunteers altered the percentage of gastric slow waves and, in another study, was associated with improved gastric emptying by vagal activation .

Despite the variable effects observed on gastric motility, TEA has been associated with significant symptom improvement in several studies. 11 diabetics underwent acupuncture with improvement in nausea and gastric dysrhythmia . In a randomized clinical trial of diabetic patients with gastroparesis using sham TEA as the control, TEA significantly shortened the gastric half-emptying time and improved symptom severity for 2 weeks after the end of the trial . In yet another study, 100 diabetics in China with dyspeptic symptoms were randomized to acupuncture 5 days a week or domperidone 30 mg daily for 4 weeks, with acupuncture leading to greater improvement in gastric emptying and reductions in plasma motilin and serum gastrin, which are higher in patients with diabetes . In a prospective observational study, 56 diabetics with mild or severe symptoms of gastroparesis were treated with TEA for 14 days. 30 out of 33 patients with an initial GCSI score <3.5 demonstrated at least a 25% improvement in their GCSI score compared to only 4 out of 23 patients who had an initial GCSI score >3.5. The 20 non-responders from both groups received the prokinetic, mosapride, and another 14 days of TEA, and this led to a significant reduction in GCSI scores with improved symptoms of nausea, vomiting, stomach fullness, and bloating. Gastric emptying measured by ¹³ C-octanoic acid breath test improved only in those diabetic patients with severe gastroparesis treated with combination therapy .

Few studies are available in individuals with idiopathic gastroparesis. In a cross-over placebo controlled study of 18 patients with idiopathic gastroparesis, needleless TEA was delivered with synchronized breathing (STEA) to assess symptom improvement and changes in gastric and vagal function. Although STEA was associated with improved gastric dysrhythmia, there was no benefit with regard to symptom improvement in the treatment group compared to the sham treated group .

More data are available from larger acupuncture studies in patients with functional dyspepsia. There is significant symptom overlap between functional dyspepsia and gastroparesis, with many motility experts arguing that they are disorders on the same pathophysiologic spectrum . Several randomized placebo-controlled trials comparing TEA to placebo, or to prokinetic medications are mentioned here. A large randomized control trial involving 712 patients in patients with functional dyspepsia demonstrated that TA was superior to sham TA as well as to the prokinetic, itopride, and was associated in significantly greater improvement in symptoms and quality of life . The influence on cerebral activity was studied in 72 patients with functional dyspepsia who were randomized to TA vs. sham TA, demonstrating a decrease in symptom index of dyspepsia (SID) score and in improved quality of life in the treatment group. Imaging done using positron emission tomography (PET) showed that there was extensive deactivation in cerebral activity in the AP group suggestive of central mechanism . A later retrospective analysis of the patients in this study determined that the patients with postprandial distress syndrome experienced greater symptomatic improvement compared to those with epigastric pain syndrome . Xu et al. performed a study to evaluate the effect of TEA on gastric accommodation and gastric motility using sham-TEA as control in patients with functional dyspepsia and showed that TEA significantly improved gastric accommodation as well as increased the percentage and power of gastric slow waves . Another single blind randomized clinical trial in Brazil examined the effect of acupuncture on the symptoms of 30 patients with functional dyspepsia. Patients were randomized into Group 1, which received TA at specific points (PC6, LI4, CV12, ST36, L3, ST44), and Group 2, which received TA at non-specific points (PC5, LI3, CV11, ST35, L2, ST43) plus drug therapy depending on the type of functional dyspepsia (FD) D they had. After 4 weeks, Group 1 demonstrated statistically significant improvement in symptoms as measured by GSRS, and quality of life. There was also a significant reduction in anxiety symptoms. Three months later, neither group had sustained values as was seen immediately after the conclusion of therapy, but still, patients in Group 1 were significantly better than those in Group 2 .

In sum, acupuncture administered at specific points appears to exert a prokinetic effect in both rodents and humans. However, the results are variable and the exact physiologic basis remains ambiguous at the present time. Regardless of its effect on gastric motility, many studies suggest that TEA improves symptoms associated with functional dyspepsia and diabetic gastroparesis. A caveat for many studies has been that the severity, or change, in gastroparesis symptoms has not always been quantified using standard surveys. Important factors to consider are that acupuncture has no significant side effects, and for that reason, may be useful as adjunctive therapy to conventional approaches for some patients with mild to moderate symptoms of GP.

Psychological intervention

The gut-brain axis describes the exchange of information between the central nervous system (CNS: brain/spinal cord) and the Enteric Nervous System (ENS: GI tract). Reflexes exist within this axis that allow bi-directional transmission of signals between the gut lumen and the brain . Descending corticolimbic signals can modulate the responsiveness of ENS reflexes, which in turn regulate and synchronize motility, secretion, and blood flow within the GI tract. A patient’s cognitive and emotional states impact physiological responses and may lower the threshold for experienced pain.

GI-directed behavioral health interventions (BHI) may help improve quality of life in some patients with functional GI disorders. After an average of seven sessions with a GI psychologist who used brain-gut psychotherapies, patients’ self-reported scores on an Irritable Bowel Syndrome-Quality of Life (IBS-QOL) questionnaire were significantly higher than baseline. Brain-gut psychotherapies consistently incorporated techniques from Cognitive Behavioral Therapy (CBT) and gut-directed hypnotherapy interventions. Female patients with disorders of gut-brain interaction (DGBI), high somatization of symptoms, and depression were found to be particularly responsive to BHI . Disorders of gut-brain interaction are often co-morbid with depression (30% of patients) and anxiety (50% of patients) , which further supports a need for integrating psychological therapies into management of GP.

Psychological treatments with greatest evidence for improving gastrointestinal symptoms include CBT, hypnotherapy, and mindfulness based therapies . These methods have been most extensively applied in patients with IBS and inflammatory bowel disease (IBD); however, since GP often presents with similar symptoms of nausea, vomiting, bloating, and abdominal discomfort, it is not unreasonable to consider utilizing them in conjunction with more conventional medical therapy or alternative therapies. CBT educates patients about the body’s natural stress response and its impacts on gastrointestinal functioning and mood. Through work with a CBT trained psychologist patients learn new coping skills, how to reduce physiological arousal, and to mediate hypervigilance through regular practice of relaxation skills. These may include diaphragmatic breathing, muscle relaxation, and self-hypnosis.

Gut directed hypnotherapy is another modality that targets the brain-gut axis by down-regulating GI sensations through normalization of pain processing and perception. In patients with functional abdominal pain and bowel complaints, this therapy has been shown to improve visceral sensitivity, gut motility, central processing, and overall psychological status . As a therapeutic technique, hypnotherapy follows a procedure which begins with an Introduction, during which patients are presented with imaginative experiences. Next, is a phase of Induction during which patients – with guided instruction – enter into an altered consciousness or ‘trance.’ At this time, the therapist makes suggestions to help patients change their subjective experience, fixed beliefs, and perceptions. With gut-directed therapy specifically, the purpose of suggestions is to control and normalize GI function . The North Carolina protocol outlines a standard seven-session hypnosis treatment approach that can be delivered verbatim for GI complaints and has been found to be beneficial in more than 80% of patients with IBS .

Electrogastrographic (EGG) biofeedback is an alternative treatment that may enhance gastric activity and benefit patients with GP. Biofeedback has been used for over 50 years to teach individuals how to control muscle activity, brain waves, autonomic nervous system (ANS) responses, and bowel/bladder habits. In this specific study’s biofeedback session, patients observed their EGG activity on a computer screen and were instructed to match their signal to a normal 3 cpm signal of gastric myoelectric activity . By using guided imagery, patients were told to relax and focus on their stomach’s activity. Compared to control subjects who did not receive biofeedback, experimental participants showed an increased percentage of 3 cpm activity over the course of 4 trials separated by 2–7 days. Although this work was done in subjects without GP, it suggests that non-diseased patients can alter their EGG responses using biofeedback. More studies are needed to determine the impact of biofeedback in patients with slowed gastric function, but it is reasonable to predict that through such treatments GP patients may be able to improve – or normalize – their motility. Similar to biofeedback, autonomic training (AT) with directed imagery through verbal instruction can decrease nausea and vomiting in patients with chronic motility disorders . Patients who had significant improvement in symptoms were those that at baseline had mild to moderate delay in gastric emptying measures and adrenergic dysfunction.

Dietary supplements and herbal formulations

In addition to addressing psychological factors through behavioral health interventions described above, some patients may find improvement in symptoms through dietary change and use of herbal supplementation. Historically, patients have been advised to adhere to a diet consisting of multiple small meals that were low in fat and non-digestible/insoluble fiber. Fatty foods slow gastric emptying and foods with high insoluble fiber (fresh fruits and vegetables) are difficult for GP patients to digest due to their often impaired inter-digestive antral motility. In a study of 56 insulin dependent diabetics with gastroparesis, a “small particle diet” significantly improved nausea, vomiting, bloating and fullness but not abdominal pain .

Plant-derived extracts and chemicals may possess pharmacologic effects and clinical benefits. Yet, claims made for such non-pharmaceutical, natural medicines are often based on empirical evidence rather than well supported scientific trials . In 1994, the US Dietary Supplement Health and Education Act (DSHEA) allowed herbal supplements to be sold without efficacy or safety testing, which may explain the lack of clear, uniform information regarding their health effects. Nevertheless, certain natural medicines are routinely recommended for various GI complaints and some have been supported by randomized control trials (RCTs).

As addressed earlier in this text, gastroparesis may present with a variety of symptoms including nausea/vomiting, early satiety, bloating, and belching. For dyspepsia and digestive problems, peppermint and caraway oils have been used for their spasmolytic effects. Frequently combined in oral preparations, peppermint with caraway has been more effective than placebo in non-ulcer dyspepsia . Other studies have found that peppermint oil reduces intragastric pressure , but did not significantly alter gastric emptying compared to placebo . Peppermint oil, which contains menthol, relaxes smooth muscle and may help with abdominal pain and spasm. The effects of menthol on symptom improvement are thought to be mediated by the melastatin8 (M8), a member of the transient receptor potential (TRP) cation channel superfamily found on sensory afferent nerves . A meta-analysis of 12 randomized trials of peppermint oil for the treatment of IBS symptoms found that peppermint oil improved global symptoms and abdominal pain as compared to placebo . However, a recent randomized trial in IBS patients using a small-intestinal release formulation or an ileocolonic release formulation of peppermint oil versus placebo for 8 weeks found that neither formulation improved abdominal pain or provided significant overall symptom relief .

Fennel oil has been used to treat functional GI symptoms. The compound anethole is found in fennel oil and a Japanese herbal medication, Anchusan. When orally administered to mice, anethole appears to improve clonidine-induced (but not normal) gastric emptying and stimulates accommodation . In IBS patients, a combination of essential fennel oil and curcumin taken for 30 days significantly decreased symptom severity scores, abdominal pain, and improved quality of life . Anetole binds to the transient receptor potential (TRP) cation channels found on sensory neurons of the dorsal root ganglia .

STW5, marketed as Iberogast®, is a European commercial preparation of 9 herbs: fresh plant extract of bitter candytuft (Iberis amara), celandine herb (Chelidonii herba), milk thistle fruit (silybum mariani frutus), balm leaf (Melissae folium), caraway fruit (Carvi fructus), licorice root (Liquiritiae radix), angelica root (Angelicae radix), chamomile flower (Matricariae flos), peppermint herb (Menthae piperitae folium) . STW5 increased proximal gastric volume, antro-pyloro-duodenal motility and gastric emptying in healthy men leading to gastric relaxation and antral motility . RCTs have demonstrated its efficacy and safety for treating symptoms of functional dyspepsia when compared to placebo . For adults, the recommended dose is 1 mL (20 drops) Iberogast® in liquid, taken 3 times per day with meals. Gastritol® Liquid is a different combination of extracts: chamomile, silverweed, licorice, angelica, blessed thistle and wormwood that is marketed for gastritis and dyspepsia. Through a local effect in the GI tract and a central effect on the stomach’s secretory and motor functions, Gastritol® is claimed to protect the stomach lining, eliminate inflammation, nausea, bloating and normalize stool and appetite . Although research is limited, after a treatment period of 2 weeks Gastritol® significantly improved GI symptoms among healthy and diabetic patients, most notably in vomiting and retching .

Ginger has proven effective for nausea and vomiting, which are two of the most frequently experienced symptoms of GP . The root is commonly ground into powder, incorporated into capsules and also made into tea. The effects on gastric function have been attributed to active compounds gingerols, specifically, 6-shogaol , which stimulates intensive calcium influxes in nodose neurons and triggers action potential discharges in most studied nodose C-fibers . This effect is blocked by TRPA-1 specific blockers.

Results from a systematic review of six RCTs suggested that ginger is better than placebo for post-operative nausea and is non-inferior to metoclopramide . Although the pooled absolute risk reduction for post-operative nausea was non-significant for 1 g ginger taken before the operation, this may be due to the small number of studies included. Ginger is also effective for car or boat motion sickness and morning sickness of pregnancy. In a systematic review of alternative medicine for treatment of nausea and vomiting of pregnancy, ginger at low doses (25–500 mg) and Vit B6 had an identical effect of mild symptom improvement. At higher doses ginger was superior to Vitamin B6. Complicating this finding, over a longer treatment period (60 days), Vitamin B6 was superior . The recommended daily dose of ginger for this use is between 1–4 g.

It has also been proposed that Vitamin D may influence gastric emptying time . At the fourth hour of a gastric emptying test (GET), every unit increase in 25-OH Vitamin D was associated with significant improvement in GET measures, when diabetic and idiopathic GP groups were combined. Within the idiopathic GP group, higher Vit B6 levels were related to significantly increased gastric emptying measures at the first hour GET, and less strongly at the second and fourth GET hours. More research is needed to examine the impact of nutritional deficiencies on ENS function and pathophysiology.

Cannabis

When traditional and herbal therapies have failed, some patients may find symptomatic relief from medical use of cannabis. Approximately 1/3 of patients with chronic nausea/vomiting actively use cannabinoids for their GP; they are usually younger with more severe, refractory symptoms . CB1 and CB2 are classic receptors distributed throughout the CNS, enteric neurons as well as nerve fibers, and terminals of the ENS. CB1 is specifically seen throughout the gut wall, which may explain some patients’ response to cannabis treatment for GI related problems. Currently, the FDA has approved the synthetic non-selective cannabinoid agonist, dronabinol, in liquid and capsule forms for the treatment of anorexia and weight loss in AIDS, and for nausea and vomiting associated with chemotherapy, in patients who have not responded to conventional antiemetics . Extraordinary case reports of off label use of cannabis-related products, like dronabinol fuel enthusiasm, as in the case of a woman with severe intestinal dysmotility, allowing her to maintain oral nutritional status after eight years of unsuccessful symptom management through conventional methods . This observation is countered by the observation that dronabinol delays gastric emptying in humans , and a study of IBS patients that found no significant effect of dronabinol on gastric, small bowel or colonic transit time as measured by radioscintigraphy .

The National Academies of Sciences, Engineering, and Medicine (NASEM) assembled a 16 member committee to perform a comprehensive literature review of benefits and harms of cannabis when used for medical conditions . Primary research and systematic review articles published after 2011 were prioritized, which resulted in >24,000 articles examined. Significant evidence was found for use of cannabinoids for chemotherapy induced nausea and vomiting as well as chronic pain, suggestive of improved symptomatic control rather than motility. More recently, dronabinol (n=36), as well as cannabidiol (n=16) and tetrahydrocannabinol (n=63) were studied for their effects on GP patients’ perceived improvement of symptoms . Of the patients assigned to each of three groups, the greatest decrease in perceived symptoms was found in the tetrahydrocannabinol group (93.5%), but improvement was also evident with cannabidiol (81.3%) and dronabinol (47.2%). Smoking was the predominant method of use in this study. One important question is whether symptom improvement with marijuana differs depending on route of administration (via capsule, liquid, or inhalation). No studies have yet compared these methods and their symptomatic improvement in GI disorders. A caveat is that chronic overuse of cannabis causes cannabis hyperemesis syndrome, which presents with cyclical vomiting and abdominal pain . While current research on cannabis seems promising, randomized control trials are necessary to gain better understanding of the role of medical cannabis, specifically for treatment of GP.