Abdominal pain in gastroparesis: Prevalence, potential causes and management

Overview of abdominal pain in gastroparesis

Gastroparesis is a chronic disorder characterized by delayed gastric emptying in the absence of mechanical obstruction . The classic symptoms of gastroparesis are early satiety, postprandial fullness, nausea and vomiting. Gastroparesis can occur in several clinical settings; it is most commonly associated with diabetes mellitus, idiopathic (that is, without a known cause) and post-surgical . The diagnosis of gastroparesis is generally made with a gastric emptying test with scintigraphy, wireless motility capsule or breath test .

While gastroparesis usually presents with nausea or vomiting, abdominal pain is also a frequent symptom in these patients . Various studies have reported a prevalence of abdominal pain to be in the range of 46%–89% in gastroparesis patients . Abdominal pain is often viewed as an atypical symptom and has been largely ignored in treating gastroparesis patients. Furthermore, the cause of pain in gastroparesis is largely unknown and it is taught that if a patient has significant abdominal pain, one should first think about other disorders besides gastroparesis. Conditions to be considered in the differential diagnosis of abdominal pain in this scenario may include peptic ulcer disease, chronic pancreatitis, biliary tract disease (gallstones or biliary dyskinesia), fibromyalgia, functional disorders such as irritable bowel syndrome and functional dyspepsia, and rarer disorders including cyclic vomiting syndrome, median arcuate ligament syndrome, superior mesenteric artery syndrome, and reflex sympathetic dystrophy .

Similar to gastroparesis, functional dyspepsia is characterized by symptoms of postprandial fullness, early satiation, or epigastric pain or burning with no evidence of structural disease on upper endoscopy . Functional dyspepsia is classified into two subgroups: postprandial distress syndrome (early satiation or postprandial fullness) and epigastric pain syndrome (pain or burning in the epigastrium) . Functional dyspepsia is a heterogeneous disorder, which is associated with various pathophysiological changes including impaired gastric emptying (either delayed or rapid), impaired fundic accommodation, visceral hypersensitivity, and infrequently, helicobacter pylori infection. There is overlap between gastroparesis and functional dyspepsia as both symptoms and gastric emptying results may meet definitions for both in some patients . Since the symptoms of functional dyspepsia are non-specific and cover gastric symptomatology and patients with idiopathic gastroparesis have similar accompanying gastric symptoms, it is not surprising that many gastroparetic patients meet criteria for functional dyspepsia. Based on a study from the Gastroparesis Clinical Research Consortium Registry (GpCRC), 86% of patients with idiopathic gastroparesis met criteria for functional dyspepsia and 91% met criteria for postprandial distress syndrome . Severity of delay in gastric emptying correlated with the severity of vomiting and loss of appetite.

The relationship of abdominal pain to delayed gastric emptying can be difficult to understand in some patients. Narcotic analgesics, sometimes used for abdominal pain, can cause symptoms of nausea and vomiting, by their central effects on the chemoreceptor vomiting center. In addition, these agents can delay gastric emptying and, in turn, cause symptoms of nausea and vomiting. The slowing of gastric emptying may result in the gastric emptying test being interpreted as delayed. Thus, in some patients with abdominal pain from non-gastroparesis etiologies who take narcotic analgesics for pain, a gastric emptying test can be delayed, not because they have gastroparesis, but because the narcotic analgesic is delaying gastric emptying. For evaluation, it is suggested that patients do not take narcotic analgesics for 48–72 hours prior to the gastric emptying test, particularly hospitalized patients receiving intravenous narcotics .

The Gastroparesis Cardinal Symptom Index (GCSI) was designed to quantitate the severity of symptoms of gastroparesis . Interestingly, abdominal pain is not one of the symptoms in the GCSI. In patient interviews for the development of the daily diary form of the GCSI (GCSI-DD), one-third of the patients with gastroparesis felt abdominal pain was an important symptom of gastroparesis . The Patient Assessment of GI Symptoms (PAGI-SYM) is a questionnaire that captures symptoms of gastroparesis, functional dyspepsia, and gastroesophageal reflux disease . The 20 question PAGI-SYM contains the 9 symptoms of the GCSI. Using the PAGI-SYM, upper abdominal pain scores in patients with gastroparesis averaged 2.21 on a scale from 0 to 5 . This value was similar to conditions more classically associated with pain including dyspepsia . The PAGI-SYM also asks about abdominal discomfort, a term that can be difficult to gauge as it may be interpreted by patients as mild abdominal pain or interpreted with other symptoms such as stomach fullness.

Prevalence of abdominal pain in patients with gastroparesis

In the GpCRC registry, abdominal pain was reported to be the predominant symptom in one-fifth of gastroparesis patients and can produce significant morbidity and utilization of health care resources . Based on some case series, the prevalence of abdominal pain in gastroparesis were initially reported to be in the range of 46–71% and many individuals state their pain is of moderate to severe intensity . The pathophysiological cause and treatment of pain in gastroparesis are largely unexplored and not well understood. There have been four large studies that have specifically characterized abdominal pain in patients with gastroparesis .

In one of the first studies focusing on pain in gastroparesis, Hoogerwerf et al. reported the prevalence of abdominal pain in gastroparesis to be 89% . This prevalence of pain was similar to that of nausea (93%) and early satiety (86%) but was greater than that of vomiting (68%). Abdominal pain was characterized as crampy, burning, or vague in character and was localized to the epigastrium in only 36% of cases. Meals exacerbated symptoms in 80% but provided relief in 15% of patients. Up to 80% of gastroparetic patients experienced some nocturnal pain.

In a study by Cherian et al, abdominal pain was present in 90% of patients with gastroparesis, a prevalence rate compared to nausea which was present in 96% . Abdominal pain was generally midline: epigastric in 43%, umbilical in 13%, and hypogastric in 11%. Intermittent abdominal pain was experienced by 62% of patients and 43% had daily abdominal pain. Many patients also complained of nocturnal pain (74%) with interference of sleep (65%). Using the 5-point PAGI-SYM symptom score, the severity of upper abdominal pain (3.04) was lower than nausea (3.57) but was greater than the severity of vomiting (2.21). Abdominal pain severity did not correlate with gastric emptying retention at 2 or 4 hours. The upper abdominal pain subscale was significantly higher in idiopathic than diabetic gastroparesis (3.36 vs 2.68) whereas the nausea/vomiting subscale showed no significant difference between the two groups. There were also significant moderate correlations between abdominal pain and impaired quality of life in multiple aspects of life and daily living. In this study by Cherian et al, abdominal pain was reported to be a little more prevalent in functional dyspepsia patients with normal gastric emptying (98.1%) when compared with gastroparesis patients (90%) . Furthermore, the severity of abdominal pain was greater in functional dyspepsia when compared to gastroparesis (3.63 vs. 3.04).

In the first study by the GpCRC focusing on abdominal pain, about 66% of the patients reported more moderate-severe abdominal pain . The presence of abdominal pain was associated with an idiopathic etiology, impaired quality of life, and increased opiate use, but not gastric emptying . Gastroparesis patients identified predominant pain as having at least as great an impact on disease severity and quality of life as in patients who rated nausea/vomiting as their predominant symptom .

Recently, the second study by the GpCRC analyzed abdominal pain by using more detailed pain assessment tools such as the Patient Assessment of Upper GI Symptoms (PAGI-SYM) questionnaire, the McGill Pain Questionnaire and the Brief Pain Inventory Short-Form (BPI-SF) . Furthermore, several other assessment tools were utilized including the Patient Assessment of Upper Gastrointestinal Disorders Quality of Life (PAGI-QOL) survey, Medical Outcomes Study 36-Item Short-Form Health Survey version 2 (SF-36v2), Beck Depression Inventory (BDI), Patient Health Questionnaire (PHQ–15), and the State-Trait Anxiety Inventory (STAI). In this study, out of 346 patients with either diabetic or idiopathic gastroparesis, 90% patients reported abdominal pain. The most common abdominal pain locations were upper midline (36%) or central midline (22%) and the quality of pain was often described as cramping or sickening in character. Increased upper abdominal pain severity was associated with increased severity of each of the nine GCSI symptoms, depression, anxiety, somatization, use of opiate medications, decreased quality of life, but it was not related to severity of delayed gastric emptying or water load ingestion .

Based on these studies, we can infer that many patients with gastroparesis have abdominal pain, which at times can have comparable severity to nausea and vomiting. Additionally, abdominal pain along with nausea and vomiting significantly correlate with an impaired quality of life. Interestingly, abdominal pain does not correlate with a delay in gastric emptying. Abdominal pain was worse in idiopathic compared to diabetic gastroparesis. Further investigation is ongoing with the NIH-funded GpCRC to identify causes of abdominal pain in patients with gastroparesis to help determine how best to treat this symptom in patients.

Pathogenesis of abdominal pain in gastroparesis

The pathogenesis of pain in gastroparesis is poorly understood, leaving treatments for this symptom largely empirical and often unsatisfactory. A limited number of investigations have addressed the underlying causes of pain in gastroparesis. It is plausible that it can be the manifestation of more diffuse entities such as autonomic neuropathy and visceral hyperalgesia .

Several studies have shown that there is no correlation between delayed gastric emptying and severity of abdominal pain in patients with gastroparesis . In a prospective observational study, the relationship between PAGI-SYM sub-scores and gastric sensorimotor dysfunction was studied in functional dyspepsia . Gastric emptying was correlated with symptom subscores for nausea/vomiting, fullness/satiety, bloating, heartburn/regurgitation, but not upper abdominal pain.

The lack of correlation between abdominal pain and gastric emptying suggests that other mechanisms may be responsible for the abdominal pain in patients with gastroparesis, such as changes in gastric accommodation, gastric distension and/or visceral hypersensitivity . In patients with idiopathic gastroparesis, the symptom pattern has been suggested to be determined by proximal stomach dysfunction rather than by the severity of delayed emptying . The prevalence of pain has been found to be similar in symptomatic individuals with normal versus impaired gastric fundic accommodation . Hypersensitivity to gastric distension was associated with higher prevalence of epigastric pain, early satiety and weight loss . Impaired accommodation was associated with higher prevalence of early satiety and weight loss. Thus, visceral hypersensitivity may be one of the factors responsible for abdominal pain in patients with gastroparesis.

In diabetics with gastroparesis, pain has been considered to be a consequence of autonomic neuropathy. However, one small study found that more severe forms of visceral afferent neuropathy were associated with fewer rather than more severe symptoms in diabetic gastroparesis .

Another possible factor to consider is chronic abdominal wall pain (CAWP) which could also be referred to as somatic abdominal wall pain. Forceful vomiting alone can cause pain from the abdominal wall related to rectus muscle strain, cramping, or spasm. CAWP can be differentiated from intraabdominal source of pain by eliciting a positive Carnett’s sign. A positive Carnett’s sign is a clinical exam finding characterized by worsening epigastric abdominal pain elicited by tightening of the abdominal wall muscles when the patient does head and shoulder lift or with leg raising maneuvers . A positive test indicates an increased likelihood of abdominal wall musculoskeletal pain and not the intraabdominal cavity pain. In a preliminary report from Gastroparesis Registry 3 participants (N=118), about 15% of the patients had a positive Carnett’s sign . These patients were predominantly female (100%), had higher nausea scores, higher fullness/satiety scores, severe lower abdominal pain, a significantly higher concomitant diagnosis of fibromyalgia, major depression, severe anxiety disorder, post-traumatic stress disorder and history of stressful life events or possible childhood trauma . Thus, in this study, a positive Carnett’s sign correlated strongly with females with previous history of sexual abuse or post-traumatic stress disorder.

In another prospective study of 32 gastroparesis patients with abdominal pain, the abdominal pain was characterized into neuropathic and nociceptive pain components and patients were assessed for hypervigilance to pain. Of 32 patients, 11 patients (35.5%) met criteria for neuropathic pain on Neuropathic Pain Questionnaire. In addition, 20 patients (62.5%) had positive Carnett’s sign suggesting somatic pain. Fifteen patients (48.4%) were hypervigilant to pain on Pain Vigilance and Awareness Questionnaire. This small study showed that of gastroparesis patients with abdominal pain, one-third have a neuropathic component to their pain whereas two-thirds have characteristics of somatic pain. Almost half of the gastroparesis patients with abdominal pain are hypervigilant to pain. Determining the underlying cause of abdominal pain and hypervigilance to pain in gastroparesis patients may assist in devising appropriate treatment strategies

These studies demonstrate that abdominal pain in gastroparesis patients could be multifactorial with significant somatic, visceral, and neuropathic components, augmented by hypervigilance and opioid use . The cause of abdominal pain in gastroparesis is often not known; hence, its treatment can be challenging. Preoccupation with or increased attention (hypervigilance) to pain is associated with perceived pain severity and psychosocial disability.

Unexplored as a factor in abdominal pain in patients with gastroparesis are central mechanisms. Using positron emission tomography, altered central nervous system processing to gastric distension has been found in patients with functional dyspepsia .

Treatments for gastroparesis and their effects on abdominal pain

Treatments for gastroparesis in general often requires a multidisciplinary approach with dietary management, use of prokinetic agents, antiemetic agents, symptom modulators and targeting the CNS. Patients not responding to these first line treatment measures can be considered for surgical treatments, which includes gastric electric stimulation and/or pyloromyotomy. Pain has been neglected in the management of gastroparesis. Unfortunately, abdominal pain can be prominent and may be the most difficult symptom to control. There have been few, if any, studies to address the effectiveness of any therapy for gastroparesis on the abdominal pain in patients with gastroparesis. Administration of the usual treatments for gastroparesis (prokinetic and antiemetic agents) may not satisfactorily treat abdominal pain .

Antiemetic medications are primarily used in the symptomatic management of nausea and vomiting in gastroparesis but do not affect gastric emptying or abdominal pain directly. The benefit of not vomiting or retching by taking anti-emetics can translate to less contractions of the abdominal wall, and hence less abdominal pain as well. Thus, reduced vomiting due to anti-emetics also reduces repeated contraction of the abdominal wall muscles, which in return could be responsible for decreased pain.

Prokinetic agents aim to improve gastric emptying. Symptoms associated with delayed gastric emptying such as nausea, vomiting, and fullness are generally targeted with prokinetic agents and may improve with treatment. Of note abdominal pain is not associated with the delay in gastric emptying. In some patients, the abdominal pain may be relieved through the prokinetic effect of drugs . Some uncontrolled series with prokinetic treatments including cisapride and domperidone have observed decreases in pain that track reductions in traditional symptoms of gastroparesis such as nausea, vomiting, and fullness . However, in general when randomized controlled trials (RCT) were performed using prokinetic medications in the past, the focus on abdominal pain as a symptom of gastroparesis was not included as a part of the symptom score analysis and follow-up. In reviewing the prokinetic-related trends, the assumption is that by reducing vomiting there could be an associated reduction in abdominal pain, perhaps augmented by improving the rate of gastric emptying as well.

Intrapyloric injection of botulinum toxin into the pylorus has been reported to provide symptomatic benefit in gastroparesis based on several case series . Botulinum toxin blocks the exocytosis of acetylcholine in cholinergic nerve endings and inhibits pyloric sphincter contraction. So it was expected to benefit patients in whom pylorospasms may be contributing to the pathogenesis of gastroparesis. However in a RCT of 23 gastroparesis patients, intrapyloric botulinum injection failed to show any significant improvement in meal-related symptom scores, GCSI or gastric emptying .

Gastric electrical stimulation is being used for treatment in patients with refractory symptoms of diabetic and idiopathic gastroparesis . The stimulation performed is not gastric pacing, but high frequency, low energy gastric electric stimulation. Although initial double blind studies showed some efficacy of gastric electric stimulation on nausea and vomiting, subsequent double blind studies have been disappointing. Long term open label studies have shown reduction of symptoms of vomiting . The pivotal double blind study revealed reduction in vomiting episodes in patients with gastroparesis, primarily patients with diabetic gastroparesis . More recent double blind studies showed only nonsignificant trends towards a decrease in symptoms of vomiting in patients with diabetic and idiopathic gastroparesis during the double blind period, but a significant reduction in symptoms in a long term (1 year) on an open label, unblinded basis . In the single-center clinical practice experience with Enterra gastric electric stimulation for treatment of patients with refractory gastroparesis at Temple University, clinical symptomatic improvement occurred in 50% of patients . Three clinical parameters were found to impact on clinical response: etiology of gastroparesis, main symptoms, and use of narcotics. Nausea and vomiting were the main symptoms that were reduced and not abdominal pain, postprandial fullness or bloating. Diabetic gastroparesis had a more favorable outcome than idiopathic patients. Patients whose main symptoms were nausea and/or vomiting experienced a more favorable response than those with abdominal pain as their main symptom. Lastly, patients not taking narcotic analgesic medications, had better outcome than those patients using narcotics at the study outset. The subgroup that did best was diabetic patients with nausea and vomiting.

Pyloroplasty has been shown to improve GE. In an observational study based on a prospective database, among the 105 gastroparesis patients who underwent laparoscopic Heineke–Mikulicz pyloroplasty, 90% of the patients had significant improvement in nausea, vomiting, bloating and abdominal pain . Favorable responses have been obtained with endoscopic pyloromyotomy (G-POEM). For patients with drug refractory gastroparesis, a combined approach of pyloroplasty with GES placement can be tried. In a prospective single-arm trial with 23 gastroparesis patients who underwent simultaneous GES implantation with Heineke–Mikulicz pyloroplasty showed that 60% of the patients normalized their gastric emptying and there was a 70% reduction in the total symptom score on follow-up . The theoretical explanation for this approach is that pyloroplasty normalizes the gastric emptying and addresses the gastric fullness and pressure issue, then GES reduces any remaining nausea which addresses the vomiting issue. The combination of these effects may also reduce the abdominal pain, by decreasing the strain and repeated contractions of the abdominal wall muscles.

Treatments for pain in gastroparesis

Specific pharmacotherapy for management of pain in patients with gastroparesis is complicated by potential drug side effects, particularly a delay in emptying and/or worsening of symptoms, thereby counteracting the benefits of prokinetic and antiemetic medications often used in these patients. Before prescribing analgesics, consideration should be given to the potential effects of the medication on gastric emptying and potential for side effects and drug interactions .

Multiple mechanisms may be involved in the pathogenesis of visceral pain . A drug that selectively targets a specific mechanism may not be able to completely resolve the pain. Severe visceral pain in gastroparesis may need to be managed using a multidisciplinary approach. Various approaches are available involving the following targets: (1) coexistent dysmotility problems; (2) peripheral receptors and neuromodulators; (3) central circuits; (4) somatic hypervigilance and related conditions; and (5) inflammatory responses.