Reviewed: Procházková K, Šejna I, Skutil J, Hahn A. Ginkgo biloba extract EGb 761® versus pentoxifylline in chronic tinnitus: a randomized, double-blind clinical trial. [published online June 1, 2018]. Int J Clin Pharm. doi: 10.1007/s11096-018-0654-4.
People with tinnitus hear sounds, often described as ringing or buzzing, when no external sources are present. It can be caused by cochlear lesions, disturbances in hearing pathways, or by metabolic, cardiovascular, or musculoskeletal disorders. Tinnitus often is treated with local anesthetics, antidepressants, benzodiazepines, drugs that enhance blood flow in the cochlea and brain, anti-inflammatory agents, or drugs that improve neuroplasticity. The ginkgo (Ginkgo biloba, Ginkgoaceae) leaf extract EGb 761 (Tebonin; Dr. Willmar Schwabe Pharmaceuticals GmbH & Co. KG; Karlsruhe, Germany) and the drug pentoxifylline are among the treatments that enhance blood flow in the brain. EGb 761 is a dry extract of ginkgo leaves (35-67:1) with 60% (per weight) acetone as extraction solvent. It is standardized to 22-27% ginkgo flavone glycosides and 5-7% terpene lactones. The authors conducted a randomized, double-blind, reference-controlled, single-center trial to compare the effects of EGb 761 and pentoxifylline on psychosocial symptoms in patients with subchronic or chronic tinnitus. They also assessed the safety and tolerability of the two treatments.
The 12-week trial was conducted at the Department of Otorhinolaryngology at Královské Vinohrady University Hospital in Prague. Male and female patients aged 30 years and older who had unilateral or bilateral subchronic or chronic tinnitus for at least three months before the onset of the study were eligible for the trial. Patients were enrolled if they had maskable tinnitus (i.e., tinnitus that can be made less annoying by external sound), if they had annoyance scores of 3 or greater on an 11-Point Box Scale, and if their score on an abridged Tinnitus Questionnaire (Mini-TQ) indicated psychological distress. Patients were recruited from September 2012 to April 2014.
The patients had subchronic or chronic tinnitus for seven years on average and had tried many remedies. In addition to the 11-Point Box Scale and the Mini-TQ, the authors used the Hospital Anxiety and Depression Scale (HADS) and the Sheehan Disability Scale, a self-rating tool that assesses how work, school, social life, and family life are impaired by panic, anxiety, phobic, or depressive symptoms. Safety and tolerability of the trial products were assessed by physical and otological examinations, electrocardiograms, laboratory tests, and vital signs. All patients who took at least one treatment dose were included in the safety analysis set (SAF). Patients in the SAF who had at least one 11-Point Box Scale measurement after baseline were included in the full analysis set (FAS).
Eligible patients were randomly assigned to take one EGb 761 tablet (120 mg) with one pentoxifylline-like placebo tablet twice daily (n = 100) or one extended-release pentoxifylline tablet (600 mg) with one EGb 761-like placebo tablet twice daily (n = 100).
In the EGb 761 group, seven patients discontinued the trial (six because of adverse events [AEs] and one for reasons not given). In the pentoxifylline group, 17 patients discontinued the trial (14 because of AEs, one who withdrew consent, one who was lost to follow-up, and one for reasons not given). One patient in the EGb 761 group and two patients in the pentoxifylline group were excluded from the FAS because of a lack of data. Based on tablet counts, compliance rates were 99.4% in the EGb 761 group and 98.8% in the pentoxifylline group.
Significant improvements in anxiety, disability, and all tinnitus-related measures were seen in both groups after 12 weeks. In the EGb 761 group, improvements were seen on the Mini-TQ (P < 0.0001) and in loudness (P = 0.0021) and annoyance (P = 0.0002) scores. In the pentoxifylline group, improvements were seen on the Mini-TQ (P < 0.0001) and in loudness (P = 0.0015) and annoyance (P = 0.0003) scores. The between-group differences were not significant. Slight, though nonsignificant, improvements in HADS depression scores were observed in both groups at 12 weeks. In patients with elevated depression scores at baseline, improvements in the Mini-TQ, loudness, and annoyance scores were seen in the EGb 761 group but not in the pentoxifylline group.
Thirty-four patients in the EGb 761 group and 29 in the pentoxifylline group had abnormal HADS anxiety scores at baseline. (The authors define “abnormal” HADS anxiety scores as those greater than 7.) After 12 weeks, those numbers decreased to 22 in the EGb 761 group (P = 0.005) and to 23 (P = 0.105) in the pentoxifylline group.
Nineteen patients in the EGb 761 group reported a total of 20 AEs, and 27 patients in the pentoxifylline group reported a total of 36 AEs. A causal relationship with the study product could not be excluded for 18 AEs in 17 patients in the EGb 761 group or for 32 AEs in 24 patients in the pentoxifylline group. None of the AEs were serious, and no clinically relevant changes in the safety measures were observed during the trial. The most frequent AEs reported in the pentoxifylline group were “gastrointestinal disorders” (n = 11) and “infections and infestations” (n = 5), and the most frequent AE reported in the EGb 761 group was “worsening of tinnitus” (n = 5).
The authors explain that treating chronic tinnitus is challenging because of its various causes and because the condition changes over time. Pharmacological and nonpharmacological approaches should be prescribed after evaluating the suspected cause of the tinnitus and the psychological reaction in each patient. In this study, EGb 761 and pentoxifylline were similarly effective in reducing the loudness, annoyance, and overall discomfort of patients with subchronic or chronic tinnitus. Fewer AEs were reported in the EGb 761 group. Limitations of this study include the use of tablet counts to determine compliance and the single-center setting.