Randomised Clinical Trial

Randomised Clinical Trial: The Effects of Pregabalin vs Placebo on Functional Dyspepsia

Isariyaphong Kotikula; Nithi Thinrungroj; Kanokwan Pinyopornpanish; Phuripong Kijdamrongthum; Apinya Leerapun; Taned Chitapanarux; Satawat Thongsawat; Ong-Ard Praisontarangkul


Aliment Pharmacol Ther. 2021;54(8):1026-1032. 

In This Article


In this study, pregabalin showed significant benefit in terms of response rate when assessed by self-reporting of adequate relief, the dyspeptic symptom score (Global Overall Symptom scale), and quality of life (the short-form Nepean Dyspepsia Index scores). This effect started at week 4 and continued through the end of the study at week 8. Patients in the pregabalin group reported notable side effects of dizziness in approximately 50% of those receiving this medication.

Currently, the main focus on the treatment of FD revolves around visceral hypersensitivity and disorders of the gut-brain axis. Neuromodulators are increasingly recommended in many guidelines despite scarce and inconsistent evidence.[16,17] In a network meta-analysis comparing various treatments in FD, TCAs were one of the most effective drugs and were the first recommended among neuromodulators. However, TCAs were more likely to cause adverse events than placebo.[24] Neuromodulators, such as delta ligand agents, have been proposed for use in functional GI disorders with very limited data. In patients with IBS, pregabalin showed significantly increased rectal distension sensory thresholds, implying it is efficacious in treating visceral hypersensitivity.[25] Additionally, pregabalin also proved beneficial in reducing IBS-related abdominal pain, bloating and diarrhoea symptoms.[26] Relevant investigation into the treatment of FD is limited to one small retrospective study which showed that gabapentin was beneficial in improving overall symptoms.[27] There is also no information on how it affects upper gastrointestinal motility. To our knowledge, the present study is the first randomised controlled trial to support the beneficial impact of pregabalin use in FD patients.

Subgroup analysis by FD subtype would be inappropriate, due to the relatively small number of patients in each subtype. This present study shows that pregabalin significantly reduces epigastric pain (P = 0.01), epigastric burning (P = 0.03) and sensation of reflux of gastric acid (P < 0.01). Similar to the results found to be associated with amitriptyline treatment,[12] our findings suggest that pregabalin treatment is predominantly effective in patients with EPS, a subtype of FD with visceral hypersensitivity as its major mechanism.

There were no serious adverse events during the study. Typically, a lower dosage of antidepressants is used in the treatment of functional gastrointestinal disorders compared to the treatment of anxiety or mood disorders, which may decrease the side effects.[28] Lower dosages might be required in Thai patients compared to Caucasians, since Thais traditionally have a lower body mass index. Therefore, in this study, we used a low dose of pregabalin (75 mg once daily before bedtime) to avoid dose-dependent adverse reactions such as dizziness and drowsiness.[29] Nevertheless, the pregabalin group had a significantly greater incidence of dizziness compared to the placebo group (51.6% vs 23.5%, P = 0.02). This side effect was tolerated by the majority of patients in that group. After the first week of treatment, only two patients in the pregabalin arm declined to complete an 8-week study due to dizziness and somnolence.

Pregabalin, like TCAs, is beneficial in the treatment of FD with pain as the predominant symptom. However, there are certain differences, such as adding extra gastrointestinal benefits and unpleasant effects. Pregabalin may be beneficial for FD patients with fibromyalgia or anxiety. TCAs may be appropriate for FD patients with comorbid depression. Both have dizziness as a common side effect, but TCAs appear to have more concerning side effects including arrhythmia risk, constipation, dry mouth and blurred vision.[17] In addition to the current guidelines, pregabalin may be considered in FD patients with predominant pain, who cannot tolerate the side effect of TCAs or patients with comorbid fibromyalgia. Gabapentin and pregabalin have comparable chemical compositions and are licensed to treat similar diseases. There is little direct evidence comparing their efficacy and safety.[30,31] However, in our trial, we chose pregabalin since it had better pharmacokinetic and pharmacodynamic properties.[32] Future research will need to find out whether differences in efficacy and safety exist between pregabalin and gabapentin.

Our study has several strengths including the double-blinded nature of the study with a parallel control group. To our knowledge, this is the first such study to demonstrate the role of delta ligand agents in FD treatment. All subjects in the study were well-characterised FD patients who fulfilled the Rome IV criteria with normal endoscopic examination and no evidence of H. pylori infection. We also strictly excluded the patients with overlapping functional GI disorders, especially patients with IBS symptoms to avoid confusion regarding the outcome of the impact of this drug in IBS patients.

Our study has several limitations which would need to be addressed in future studies. First, our study was conducted in a referral university hospital, which could limit the generalisation of the results to other settings. Second, the study was conducted during the COVID-19 pandemic period, therefore, participant recruitment was challenging despite our intensive efforts and slightly fewer than the expected number of patients (72 of 84) were enrolled in the study. The difference of the outcomes in the experimental arm and controlled arm should be interpreted with caution and the evaluation of some secondary outcomes could be underpowered, and the subgroup analysis of FD subtype could not be done due to the limited number of participants. The larger prospective studies are warranted in order to confirm the benefit of this treatment. Third, a physiological study to investigate the effect of delta ligands on GI motility was not performed in this study. Finally, this trial evaluated the effect of an 8-week period of pregabalin treatment, thus, the efficacy and adverse effects of prolonged treatment, or after discontinuation of the drug was not evaluated.

In conclusion, this prospective, randomised, double-blind, placebo-controlled clinical trial showed significant benefits of pregabalin in the treatment of FD patients who were H. pylori-negative and non-responsive to a PPI, especially in patients with predominant epigastric pain syndrome. The most common side effect was dizziness, which appeared to be tolerated well after the first week of treatment.