Although nausea, vomiting, early satiety, and postprandial fullness are the main symptoms of gastroparesis, abdominal pain can be a prominent symptom in some patients with gastroparesis. Treatment of abdominal pain in patients with gastroparesis can be particularly difficult, as often the cause of the pain is not known and some of the treatments used for the pain may impact adversely on gastric emptying and other symptoms of gastroparesis. This chapter discusses the pathophysiology of abdominal pain and the management of abdominal pain in patients with gastroparesis
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.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Several medication classes offer theoretical benefits for reducing pain in the gastroparesis patient. Nonsteroidal anti-inflammatory drugs (NSAIDs) ameliorate gastric slow wave dysrhythmias in healthy human subjects . Oral indomethacin and intravenous ketorolac have been reported to resolve slow wave abnormalities in diabetics and patients with dyspeptic symptoms . In general, NSAIDs are given on an intermittent basis for mild to moderate abdominal pain. Although selected patients can be considered for these drugs, their routine use on a daily basis cannot be advocated due to their potential for side effects. One is the potential development of peptic ulcers which can be combated by simultaneous use of proton pump inhibitors. The other is worsening renal function .
Mild abdominal pain in gastroparesis is frequently treated with antispasmodics such as dicyclomine or hyoscyamine by many clinicians . These medications are commonly used to treat abdominal pain in IBS, and with the epigastric location of abdominal pain also overlapping the location of the transverse colon, then that also justifies use of anticholinergics as a trial . It is hypothesized that the benefits of these medications are due to their anticholinergic effects, resulting in intestinal smooth muscle relaxation.
Symptom modulators are medications used to reduce symptoms without addressing delayed gastric emptying. This is in contrast to prokinetic agents which act to improve delayed gastric emptying. Antidepressants and pain modulators such as gabapentin and pregabalin exhibit beneficial effects in reducing chronic abdominal pain of varied etiologies, but their effects on gastroparesis pain are largely unknown and still being assessed . These agents can also help improve nausea and vomiting. Investigations focusing on the specific effects of these and other treatment modalities on abdominal pain in gastroparesis are warranted.
Tricyclic Antidepressants (TCAs)
Tricyclic antidepressant (TCA) medications in low doses may reduce pain associated with gastroparesis as much as they do in other forms of neuropathic pain . TCAs have been suggested to decrease nausea, vomiting and abdominal pain in patients with functional GI disorders and in patients with diabetic gastroparesis . The mechanisms on how TCAs reduce gastrointestinal symptoms are unknown, but are believed to be centrally mediated . It has been proposed that low doses of TCAs, such as amitriptyline reduce sensory transmission and reduce visceral hypersensitivity. On the other hand, TCAs can also slow gastric emptying by virtue of their anticholinergic activity.
TCAs are classified into two groups based on their structure: tertiary amines and secondary amines. Tertiary amines, including amitriptyline, imipramine, doxepin have more anticholinergic activity and more side effects. Secondary amines, including nortriptyline and desipramine have less anticholinergic activity and fewer side effects. Atypical TCAs include trazodone. In general, when treating patients with gastroparesis, TCAs with lower anti-cholinergic activity such as desipramine or nortriptyline are preferably tried first and started at low doses. A reasonable starting dose for a tricyclic agent is 10–25 mg at bedtime. If benefit is not observed in several weeks, doses are increased by 10- to 25-mg increments up to 50–75 mg. Side effects may require a change in medication in some patients .
In one retrospective analysis of open label treatment, tricyclic antidepressants reduced symptoms in patients with functional vomiting . The effective dose averaged 50 mg/day, which is lower than the dose used for depression. In two studies based on functional dyspepsia patients, low-dose tricyclic antidepressants decreased dyspeptic symptoms and abdominal pain . In a retrospective evaluation of diabetic patients with nausea and vomiting, low dose TCAs provided better symptom reduction in patients who had an unsatisfactory response to prokinetic drugs . Nearly one-third of patients exhibited delayed gastric emptying, suggesting that the presence of impaired motor function is not a contraindication for tricyclic antidepressants.
Desipramine was helpful on a per protocol basis, but not on an intention to treat basis, in female patients with functional bowel disorders, primarily irritable bowel syndrome . In this desipramine study, dose escalation occurred every week – initial dose was 50 mg orally every night at bedtime, then 100 mg, then 150 mg/day. On the per protocol basis, the response rate to desipramine (69%) was greater than to placebo (49%) when patients who did not take their medication due to side effects or other reasons were excluded. Adverse events occurred with desipramine in 17% of patients.
The GpCRC Nortriptyline study for patients with Idiopathic Gastroparesis (NORIG Trial) showed that nortriptyline treatment did not improve overall symptoms, as defined by the primary outcome measure (GCSI total score) over a 15 week period . However, there were some interesting findings in this study. After the initial 3 weeks of treatment, there was improvement in nausea and abdominal pain at the initial low dose of nortriptyline (10 mg), but not sustained over time as dosing was increased. At 15 weeks of treatment, higher doses of nortriptyline were associated with improvements in appetite, satiety, and body weight. Another important aspect of tricyclics is that they have been shown not to inhibit gastric emptying, while at the same time having other positive effects .
Mirtazapine is an antidepressant with central adrenergic and serotonergic activity and direct anti-emetic activity via 5-HT3 antagonist activity . In a randomized controlled trial with functional dyspepsia patients, mirtazapine significantly improved early satiation, quality of life, gastrointestinal-specific anxiety, nutrient tolerance, and weight loss . In an open-label study of 30 gastroparesis patients, mirtazapine dosed at 15 mg daily significantly improved nausea, vomiting, retching and perceived loss of appetite . It may be particularly useful in gastroparesis patients with abdominal pain accompanied by nausea, loss of appetite and weight loss.
SSRIs, SNRIs, SSNRIs
Other antidepressant classes including selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), and combined selective serotonin/norepinephrine reuptake inhibitors (SSNRI) may have benefits as well, however there are no data on their actions on visceral nerve function. One of the most commonly utilized antidepressant under this class of medications is Duloxetine (SSNRI), which is often used in treating abdominal pain in gastroparesis patient. Other than being used in major depressive disorder and generalized anxiety disorder, it is also used for treatment of diabetic neuropathic pain and chronic musculoskeletal pain . The medications that are effective in the treatment of diabetic polyneuropathy are considered to have benefit in the management of pain related to gastroparesis since both these conditions have similar pathophysiology. In three randomized placebo-controlled trials, Duloxetine at doses of 60–120 mg/day have shown to result in significant improvement in diabetic neuropathic pain when compared with placebo. The reported side effects include nausea, somnolence, dizziness, decreased appetite, or constipation .
Various SSRIs and SSNRIs, such as venlafaxine (SSNRI), sertraline (SSRI), and escitalopram (SSRI), did not show benefit over placebo in large well-designed clinical trials in patients with functional dyspepsia . A Cochrane systematic review for venlafaxine in the treatment of painful diabetic neuropathy, which included six RCT’s (N=460), found little compelling evidence to support the use of venlafaxine in neuropathic pain . The SSRI paroxetine has been shown to improve gastric accommodation and accelerate small intestinal transit in healthy adults but there are no data currently to support its use in patients with bowel disorders .
A double-blind, RCT evaluated the effects of serotonergic psychoactive agents on gastrointestinal functions in healthy human subjects comparing four regimes: buspirone (10 mg twice daily); paroxetine (20 mg daily); venlafaxine-XR (75 mg daily); or placebo for 11 days . No effects on gastric emptying or colonic transit were observed with any agent. Small bowel transit of a solid meal was accelerated by paroxetine. Buspirone decreased postprandial aggregate symptom and nausea scores. Venlafaxine-XR increased the postprandial change in gastric volume. Thus, the study concluded that buspirone, paroxetine, and venlafaxine-XR affect upper gastrointestinal functions in healthy humans.
5-hydroxytryptamine (5-HT) 1 A receptor agonists:
Buspirone is an anxiolytic medication which acts via selective serotonin 5-HT1A partial agonist action and it has been shown to relax the proximal stomach in healthy individuals . A subgroup of gastroparesis patients have lack of accommodation or receptive relaxation of the gastric fundus with initiation of eating. Subsequently, food is prematurely emptied into the antrum before the usual slower release. Hence there is a feeling of fullness and abdominal pain accompanied by premature satiety and nausea. This pathophysiological mechanism has been addressed by using buspirone in Europe. In a small RCT of 17 patients with functional dyspepsia, buspirone dosed at 10 mg three times daily, significantly reduced the overall severity of symptoms of dyspepsia and a reduction in individual symptoms of postprandial fullness, early satiation, and upper abdominal bloating . The buspirone significantly increased gastric accommodation and delayed gastric emptying of liquids but did not alter the rate of gastric emptying of solids or sensitivity to gastric distention . Currently the National Institutes of Health (NIH) GpCRC is conducting a double blinded trial (BESST trial – Buspirone for Early Satiety and Symptoms of Gastroparesis) to investigate whether buspirone is better than placebo in addressing this subgroup of gastroparesis patients with impaired gastric accommodation, which is assessed by measuring fundic emptying during a gastric emptying study with a standard scintigraphic egg beater meal.
In a multicenter Japanese study, another 5-HT1A agonist tandospirone was studied in 144 functional dyspepsia patients over a 4-week period. Patients in the tandospirone group demonstrated alleviation of epigastric pain and discomfort when compared with the placebo group, independent of changes in anxiety and depression levels .
Antipsychotics such as haloperidol and olanzapine have been well studied for chronic nausea and vomiting in the palliative care setting . Recently there has been an increased interest in the utility of haloperidol in the management of acute symptoms, especially in patients with gastroparesis. In a retrospective case-matched study, 52 patients with diabetic gastroparesis who received haloperidol 5 mg intramuscular injection for the management of nausea, vomiting, and abdominal pain in emergency departments were identified . These patients were case-matched with themselves on the most recent previous visits for the same symptoms but without haloperidol administration. The haloperidol group had a significant reduction in opioid requirements and reduced hospital admission rates for gastroparesis. In a RCT of gastroparesis patients with acute exacerbation, the treatment group received 5 mg of haloperidol in addition to the conventional treatment (N=15) and the control group received a placebo in addition to the conventional treatment (N=18). One hour after the treatment patients in the haloperidol group had a significant reduction in both nausea and abdominal pain when compared with the placebo group .
Antiepileptic agents such as gabapentin and topiramate are effective in the treatment of peripheral neuropathic pain. Although they have unknown actions in patients with pain associated with gastroparesis, they are frequently used to treat pain in diabetic patients with peripheral neuropathy . Antiepileptic agents have not been widely used in visceral pain, except for the gabapentinoids . Although each antiepileptic agent has different mechanisms of action, they have some common features which include: sodium channel blockade, inhibition of glutamatergic transmission, and increasing gamma aminobutyric acid (GABA) concentration. These agents have much less effect on gastrointestinal motility and could be a very valuable therapeutic option.
Gabapentin binds to the α-2 δ subunit of voltage-gated calcium channels preventing release of nociceptive neurotransmitters including substance P, norepinephrine, and glutamate. It is used as an effective analgesic for patients with neuropathic pain and chronic pain syndromes. Gabapentin is approved for diabetic peripheral neuropathy . Diabetic peripheral neuropathy is a common complication of diabetes that can cause significant morbidity and mortality . Antiepileptic drugs are an effective treatment for various forms of neuropathic pain of peripheral origin, although they rarely provide complete pain relief . Sensorimotor neuropathy is marked by pain, paresthesias, and sensory loss. Gastroparesis is the most debilitating complication of gastrointestinal autonomic neuropathy. The pathology of diabetic neuropathy involves oxidative stress, advanced glycation end-products, polyol pathway flux, and protein kinase C activation; all contribute to microvascular disease and nerve dysfunction. Glycemic control remains the foundation of prevention and the prerequisite of adequate treatment. Diabetic neuropathy is a multi-faceted complication of diabetes that can be managed symptomatically with an array of drugs. For symptom management, current evidence from clinical trials supports the use of desipramine, amitriptyline, capsaicin, tramadol, gabapentin, bupropion, and venlafaxine. Trials have also shown efficacy of gabapentin and pregabalin for post-herpetic neuralgia and painful diabetic neuropathy . These drugs can be uptitrated as tolerated. Gabapentin is typically started at 100 mg three times a day dose and can be slowly uptitrated to a dose of 300 mg three times a day, with maximum doses of 1.2 g in three divided doses (total 3.6 g) utilized, while being mindful of the patient’s renal function . Common reported side effects included dizziness, somnolence, weight gain, and peripheral edema .
Lamotrigine, carbamazepine and oxcarbazepine are potential alternatives for the treatment of painful diabetic neuropathy . These agents should be titrated slowly. Carbamazepine is the drug of choice for trigeminal neuralgia; however, oxcarbazepine and lamotrigine are potential alternatives. There is need for large-scale RCT to evaluate the efficacy of antiepileptic drugs in neuropathic pain. Long-term follow-up is needed to establish the long-term efficacy of antiepileptic drugs in neuropathic pain. Topiramate, did not show evidence of efficacy in diabetic neuropathic pain based on a Cochrane systematic review which included 3 RCT’s and hence topiramate not recommended .
Careful use of opiates may need to be considered for treatment of refractory pain in selected patients. Unfortunately many patients with pain do not respond to more conservative therapies and are given intermittent or chronic therapy with opiate agents for pain control . In general, opiates are good for acute, short duration pain, such as from a surgical procedure. Although narcotic agents produce generalized analgesia, their efficacy in gastroparesis is unproved. Furthermore, opiates exert potent inhibitory effects on gastrointestinal transit inhibiting gastric emptying and colonic transit . Chronic narcotic use may result in tolerance to its analgesic effects, physical dependence, and addiction. Thus, the routine use of opiate agents for the management of pain with gastroparesis is not advocated.
Many patients with gastroparesis use opioids for pain control. In the GpCRC registry, 41% of 583 gastroparesis patients were taking opioids . Abdominal pain was the main reason for prescription in 61% of patients taking opioids. Mean scores for gastroparesis, nausea/vomiting, bloating/distention, abdominal pain, and constipation scores were higher in opioid users. Opioid use was associated with greater levels of gastric retention, worse quality of life, increased hospitalization, and increased use of antiemetic and pain modulator medications. In addition, opiates also has an independent side effect of nausea and vomiting. There was no difference in the prevalence of opioid use between diabetic and idiopathic gastroparesis (46% vs. 39%, P =0.15). Opiates, although might be helpful for acute traumatic or postsurgical pain, it is not recommended for long term use. Most treatment trials in gastroparesis limit the use of opiates for study subjects. In the current environment of limiting use of opiates due to their side effects, the number of gastroparesis patients taking opiates will hopefully decrease.
The weak opiate agonist tramadol, which can also affect serotonin and norepinephrine reuptake, appears to be a reasonable first choice. Tramadol is a centrally acting opioid analgesic, used in treating moderate to severe pain. Tramadol possesses weak agonist actions at the mu-opioid receptor, releases serotonin, and inhibits the reuptake of norepinephrine and serotonin . In contrast to morphine which slows gastric emptying, tramadol seems to have little effect on gastric or small bowel transit . However, many patients do not have optimal control of pain with this agent if the pain is moderately severe . Starting this class of medication, unfortunately can lead to progression to use of more potent opiate analgesics, with their associated side effects.
Some patients unfortunately require narcotic opiate analgesics for management of pain. These agents not only cause a delay in gastrointestinal transit, but also have the potential for tolerance, dependence, and addiction . In addition, side effects, particularly constipation can occur. Longer acting compounds such as methadone or continuous release preparations such as transdermal fentanyl may elicit less constipation than other narcotics .
A current area of drug development is the generation of peripheral opioid receptor antagonists which block peripheral effects of narcotic drugs but preserve the central analgesic effects . A study of the novel peripheral mu-opiate receptor antagonist alvimopan observed reversal of the inhibitory effects of codeine on the small intestine and colon but not the stomach . Methylnaltrexone, a mu-opioid receptor antagonist, has less penetration into the CNS and is used for refractory constipation in patients taking narcotic analgesics . Subcutaneous methylnaltrexone is recommended to patients who are on chronic narcotics, to neutralize the negative motility effect of narcotics on the gastric and colonic smooth muscles. In a placebo controlled RCT of 133 patients with opioid induced constipation, patients who received subcutaneous methylnaltrexone (dosed at 0.15 mg/kg of body weight) had significantly higher rates of laxation with a significantly shorter median time to laxation, when compared with the placebo group . It did not affect central analgesia or precipitate opioid withdrawal. In a randomized, double-blind, crossover placebo-controlled study, healthy volunteers were given either placebo, morphine or methylnaltrexone and morphine concomitantly . In this study morphine delayed the gastric emptying by four times the normal, whereas adding the antagonist methylnaltrexone reversed this effect almost fully . The most common side effects of methylnaltrexone include abdominal pain, diarrhea, flatulence, and nausea. Randomized trials for methylnaltrexone in gastroparesis are lacking.
A condition that needs to be recognized by physicians in patients treated with chronic opiate analgesics is narcotic bowel syndrome, a condition of opioid bowel dysfunction that is characterized by chronic or frequently recurring abdominal pain that paradoxically worsens with continued or escalating dosages of narcotics . Narcotic bowel syndrome can occur in patients with no prior gastrointestinal disorder who receive high dosages of narcotics after surgery or acute painful problems, and among patients with functional gastrointestinal disorders or other chronic gastrointestinal diseases. This disorder is a manifestation of enhanced pain perception through hyperalgesia effects of chronic opioid administration. The key to the diagnosis of narcotic bowel syndrome is the recognition that chronic or escalating doses of narcotics lead to continued or worsening symptoms rather than benefit. Continued treatment with narcotics leads to a vicious cycle of pain, use of more narcotics, and continued or worsening pain. Treatment involves early recognition of the syndrome and graded withdrawal of the narcotic according to a specified withdrawal program with the institution of medications to reduce withdrawal effects (tricyclic antidepressants, benzodiazepines, and clonidine).
Kappa opioid agonists have been studied for treatment of GI symptoms, primarily in patients with functional disorders. Asimadoline is a potent kappa-opioid receptor agonist, which reduced satiation and enhanced postprandial gastric volume in female volunteers . However, there were no significant effects on gastrointestinal transit. In a clinical trial of 40 patients with functional dyspepsia, asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, in a subgroup analysis of patients with higher postprandial fullness scores, 0.5 mg of asimadoline significantly decreased satiation and daily postprandial fullness severity over a period of 8 weeks.
Ketamine, an inhibitor of N-methyl- d -aspartate (NMDA) receptors which reduces central sensitization, is being investigated as an alternative for narcotic analgesics in postoperative pain and neuropathic pain . NMDA receptors are involved in the amplification of pain signals, the development of central sensitization, and in the development of opioid tolerance and dependence . Low-dose ketamine (<1 mg/kg) has been shown to have opioid-sparing effects, potentiate the analgesic effect of opioids, and to attenuate development of centralized chronic pain states . In a systematic review of 11 studies using low dose ketamine in emergency departments, ketamine was as effective as opioids for acute pain management . It was also effective in opioid tolerant patients and had fewer adverse events. In a large retrospective study (N=533, 33% had abdominal pain) which studied the use of low dose ketamine for acute pain management in emergency departments showed that ketamine was effective in the management of acute pain with no serious adverse events . In this study 3.5% patients experienced transient psychomimetic or dysphoric reactions (hallucinations, agitation, unusual behavior), 1.5% developed transient hypoxia and 1% had severe emesis. So far, ketamine has not been specifically studied in gastroparesis. However, it is a promising alternative to opioids for the treatment of acute abdominal pain in gastroparesis, but future studies are required to explore the role of ketamine in gastroparesis.
Targeting sympathetic pathways
Clinical observations suggest that clonidine, an alpha-2 adrenergic agonist, may improve diabetic gastropathy symptoms . Clonidine exhibits visceral anti-nociceptive effects, but its effects on pain with gastroparesis are uncertain . Clonidine, given as a single dose of 0.3 mg orally, has no gastric prokinetic effects . Thus, it may act on gastric afferent innervation, or more likely at a central site to reduce nausea and vomiting.
A patient is described with relief of pain using intravenous phentolamine in a patient with chronic idiopathic gastroparesis . The mechanism of phentolamine is believed to be receptor blockade at alpha-1 adrenergic receptors and therefore inhibition of the peripheral sensitizing effects of circulating norepinephrine. Intravenous phentolamine has been used as a marker for and treatment of syndromes involving sympathetically maintained pain.
The celiac and superior mesenteric ganglia provide postganglionic sympathetic innervation to the stomach and small intestine . Neurolytic celiac plexus blocks are being performed for the treatment of chronic abdominal pain from intra-abdominal malignancy and from benign processes such as chronic pancreatitis . Celiac plexus block probably interrupts visceral afferent input . The procedure entails the installation of ethanol and bupivacaine into the plexus via fluoroscopic, computed tomography or endoscopic ultrasound guidance. This procedure has been used anecdotally in patients with abdominal pain and gastroparesis.
Role of marijuana
In today’s environment, the orexigenic, antinauseant and pain-relieving properties of marijuana attract many patients with chronic nausea and vomiting symptoms such as in gastroparesis. Marijuana use was reported in 11.7% of gastroparesis patients in a pragmatic research study from the GpCRC gastroparesis registry . Use was similar among patients with delayed and normal gastric emptying and in idiopathic and diabetics. Marijuana users had higher nausea/vomiting (2.68 vs 2.08) and higher upper abdominal pain (3.50 vs 2.88). The higher severity of symptoms in the patients using marijuana were interpreted as higher symptomatic scores leading to the use of marijuana for treatment, although the data could be interpreted as the marijuana use might have led to an increase in symptom severity. Most patients using marijuana had chronic symptoms (80%) and a minority had cyclic symptoms (20%). Among marijuana users, 51% had been using this for more than 2 years, 47% of patients using this once or more per day, and 81% of patients rated their benefit from marijuana as better or much better. The synthetic analog, dronabinol, used by a small minority, is comparable in efficacy to marijuana. In the above mentioned GpCRC study, 4.4% of the cohort was using dronabinol, among which 56% were using dronabinol for 1–6 months, with 74% reporting benefit as better or much better. Marijuana users had increased anxiety, panic indices which have been reported in other studies of marijuana users. Thus, a significant minority (12%) of patients with symptoms of gastroparesis use marijuana. Patients with severe nausea and abdominal pain were more likely to use marijuana and perceive it to be beneficial for their symptoms. Physicians should inquire about use of marijuana and other cannabinoids in their patients.
It should be remembered that marijuana, while increasing appetite, actually delays gastric emptying and can be the explanation for delayed gastric emptying results by scintigraphy testing . Hence, urine marijuana screens should be considered when assessing gastric emptying studies.
Targeted treatment of abdominal wall pain
A positive Carnett’s sign is highly suggestive of somatic abdominal wall musculoskeletal pain. The following strategies are recommended in patients with abdominal wall pain :
Transdermal Lidocaine patch(es) over the epigastrium (12 hours on and 12 hours off)
Combination therapy with a TCA or even psychological or psychiatric co-therapy – depending on what was elicited from stress, depression, post-traumatic stress disorder or abuse.
Cutaneous nerve block
Treatment of abdominal bloating and distention
Gastroparesis patients with increased abdominal bloating and distention, may need to be tested for SIBO. SIBO, as detected with lactulose breath testing (LBT), may occur in up to 60% of patients with gastroparesis as a concomitant diagnosis . The mainstay of SIBO treatment are antibiotics to reduce small intestinal bacterial load. The choice of antimicrobial regimens are based on the pattern of bacterial overgrowth. In patients with hydrogen predominant bacterial overgrowth, the preferred antibiotics include rifaximin or a combination of metronidazole and ciprofloxacin or tetracycline. In patients with methane- predominant bacterial overgrowth, the preferred antibiotics include rifaximin or a combination of metronidazole / ciprofloxacin with neomycin. These patients are treated for a total of 2 weeks with rifaximin and other aforementioned antibiotic regimens. Also, follow up with one tablespoon per day of apple cider and vinegar – or vinegar with lemonade – or grapefruit juice can help acidify the small bowel. Other additional recommended measures include use of probiotics, a low FODMAP diet, and the slow tapering of proton pump inhibitors (PPI).
Acupuncture and biofeedback can also be very helpful in these conditions, and with few side effects . A Cochrane metaanalysis which included 12 studies showed that a greater proportion of patients who underwent acupuncture had short term improved symptoms (4–12 weeks) when compared with patients who received gastrokinetic medications (N=963, Risk Ratio=1.25; 95% Confidence Interval 1.17–1.33, I 2 =8%). However, the authors reported that the study should be interpreted with caution due to unclear overall risk of bias. Possible future directions include the increased use of dorsal cord stimulators, and repetitive transcranial magnetic stimulation .
This chapter has discussed abdominal pain in gastroparesis – its prevalence, pathophysiology, and treatment. It is evident that patients with gastroparesis can have abdominal pain. Studies suggest that abdominal pain occurs in a large number of patients with gastroparesis. In some patients with gastroparesis, abdominal pain can be the prominent symptom, rather than nausea and vomiting. Treatment of abdominal pain in gastroparesis is difficult, as is any type of pain. Some of the treatments may adversely impact on gastric emptying and other symptoms of gastroparesis.