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 .

Antispasmodics

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.

Psychotropic agents

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.

• A.
  

  Antidepressants:

  
  
  
  
  • i.
    

    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 .

    
    
  • ii.
    

    Atypical Antidepressants

    
    

    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.

    
    
  • iii.
    

    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.

    
    
  • iv.
    

    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 .

  
  
• B.
  

  Antipsychotics

  
  

  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 .

  
  
• C.
  

  Antiepileptic Agents

  
  

  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 .

Opiate analgesics

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

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 :

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  Transdermal Lidocaine patch(es) over the epigastrium (12 hours on and 12 hours off)

  
  
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  Heating pads

  
  
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  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.

  
  
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  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

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 .