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By David Kiefer, MD
Clinical Assistant Professor, Department of Family Medicine, University of Wisconsin; Clinical Assistant Professor of Medicine, Arizona Center for Integrative Medicine, University of Arizona, Tucson
Dr. Kiefer reports no financial relationships relevant to this field of study.
SYNOPSIS: Twelve weeks of twice-daily Ginkgo biloba extract improved symptoms as effectively as pentoxifylline in 200 adults with chronic tinnitus.
SOURCE: Procházková K, Šejna I, Skutil J, et al. Ginkgo biloba extract EGb 761® versus pentoxifylline in chronic tinnitus: A randomized, double-blind clinical trial. Int J Clin Pharm 2018;40:1335-1341.
Tinnitus is a symptom that can be acute or chronic and features numerous etiologies.1 It is notoriously difficult to treat, with some of the options including noise masking, pharmaceuticals (tricyclic antidepressants, selective serotonin reuptake inhibitors, pentoxifylline, and steroids), acupuncture, and cognitive behavioral therapy. Integrative modalities (including herbal medicine) step into the void of consistently effective therapies. One of the botanicals most evaluated for tinnitus is ginkgo (Ginkgo biloba, Family Ginkgoaceae). Procházková et al pitted ginkgo vs. one pharmaceutical option, pentoxifylline, both of which are thought to increase cochlear and cerebral blood flow.
The researchers recruited people with chronic tinnitus from an ear, nose, and throat clinic in the Czech Republic. Inclusion criteria included at least 30 years of age, tinnitus of at least three months’ duration, tinnitus able to be masked by noise, a score of at least a 3 (out of 11) of noise annoyance, a score of at least a 5 on the abridged Tinnitus Questionnaire (Mini-TQ), and gave informed consent. Exclusion criteria included tinnitus from pharmaceuticals, any current tinnitus treatment, and a variety of severe medical conditions.
Study participants were randomized to receive, twice daily, either one 120 mg tablet of the standardized G. biloba extract EGb 761 and a placebo tablet meant to look like pentoxifylline, or a 600 mg tablet of pentoxifylline and a placebo tablet meant to look like EGb 761. EGb 761 is an extract that has been subject to numerous clinical trials for a variety of medical conditions, and is standardized to 22-27% flavone glycosides and 5-7% terpene lactones, two of the groups of phytochemicals thought to provide ginkgo’s physiologic effects. Both participants and study personnel were blind to the groups’ allocation and treatments received.
Daily, study participants rated the tinnitus loudness (from 0 “no tinnitus” to 10 “extremely loud”) and annoyance (from 0 “not annoying at all” to 10 “unbearably annoying”); these were the primary outcomes. Participants completed several other questionnaires at the beginning and end of the 12-week period: the abridged Mini-TQ, a 12-item scale designed to capture some of the psychological distress associated with tinnitus; the Hospital Anxiety and Depression Scale (HADS), which analyzes symptoms as the name implies; and the Sheehan Disability Scale (SDS), used to measure how psychological symptoms affect a person’s life.
The authors randomized 200 people, with 100 in each group. Seven members of the ginkgo group stopped their therapy, and 17 members of the pentoxifylline group dropped out. One ginkgo participant and two pentoxifylline participants were not analyzed because there were no data post-baseline. Demographics and baseline scores were similar between the two groups pre-intervention. Of note, all study participants were white, the average age was 54 years, and 59% were women.
The results revealed no difference between the two treatment groups, and both groups improved over the three months. Weekly median scores in the various scales used were statistically analyzed to show these changes. The authors conducted subgroup analyses of the participants based on their HADS depression and anxiety scores. For those participants with a baseline HADS depression score ≥ 8 (indicating subclinical or clinical depression), there was a statistically significant improvement in Mini-TQ, loudness, and annoyance after 12 weeks that was not seen in the pentoxifylline group. Similarly, there were some participants with abnormal HADS anxiety scores at baseline (34 people in the ginkgo group, 29 people in the pentoxifylline group). After 12 weeks, fewer people in the ginkgo group remained with clinical anxiety vs. those who remained in the pentoxifylline group (n = 22, P = 0.005 vs. n = 26, P = 0.105).
Adverse effects occurred more often in the pentoxifylline group (27 participants, 36 adverse events) than in the ginkgo group (19 participants, 20 adverse events). The most common adverse effects were gastrointestinal (n = 11 in the pentoxifylline group) and worsening of tinnitus (n = 5 in the ginkgo group).
This study seems to add a tool to the tinnitus treatment toolbox. Compared to a pharmaceutical, a commonly used and studied formulation of G. biloba leaf fared as well in several parameters meant to follow the symptoms of tinnitus and its effects on mental health and lives in general. Particularly interesting is the possible advantage of ginkgo over pentoxifylline in terms of benefit and safety. With respect to benefit, that subset of patients with pre-existing anxiety or depression fared better with ginkgo, and ginkgo seemed to be better tolerated overall. These are important findings, especially as clinicians help patients negotiate the risk-benefit decision-making process for pharmaceutical or dietary supplement options.
This is the optimistic view of these study results. On the more hesitant side is the fact that there was no placebo group. Each group could have simply improved because they each received, and knew they were receiving, something. A true clinical improvement that could be ascribed to a given intervention can be shown only in comparison to a placebo group, which was not included in this study. Sometimes, new treatments are compared to known, standard-of-care treatments — in a study such as this one — in what are known as “noninferiority studies,” but pentoxifylline does not fall into the category of an effective tinnitus treatment. As a medicine that may act to promote blood flow, it seemingly would be useful only for people suffering from vascular-type tinnitus, but there are many types of tinnitus; this distinction was not detailed in the study. Furthermore, in the introduction of the paper where pentoxifylline is mentioned, the reference2 does not discuss pentoxifylline as a treatment option. Again, a placebo group would be needed, not a noninferiority study of a marginal treatment option.
Regarding clinical applicability, the 100% Caucasian demographic clearly limits extrapolation of these results to most clinicians’ patient panels. The use of more validated, clinical metrics for depression and anxiety, such as the PHQ-9 and GAD-7, respectively, could have illustrated changes to which practicing clinicians could better compare their current therapies.
The G. biloba extract used (EGb 761) and dose (120 mg, twice daily) are well-accepted treatments for several health conditions, including tinnitus. The researchers picked the correct formulation of this plant, and did so with no conflicts of interest nor funding concerns. It was an impressive effort to study this plant for a difficult-to-treat condition, and a few interesting findings resulted. Next, it will be important to follow up these results in a double-blind, placebo-controlled trial. Until those results arrive in the medical literature, given the few other options, clinicians could consider a ginkgo treatment course for sufferers of chronic tinnitus who are free of contraindications (i.e., worrisome potential plant-pharmaceutical interactions).
Financial Disclosure: Internal Medicine Alert’s Physician Editor Stephen Brunton, MD, is a retained consultant for Abbott, Acadia, Allergan, AstraZeneca, Avadel, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Mylan, and Salix; he serves on the speakers bureau of AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, and Novo Nordisk. Peer Reviewer Gerald Roberts, MD; Editor Jonathan Springston; Editor Jason Schneider; Editorial Group Manager Leslie Coplin; and Accreditations Manager Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study.