Review question
Which treatments are effective in improving the symptoms associated with oral submucous fibrosis?
Key messages
– The overall results are mixed but indicate that using antioxidant medications may be useful to treat restricted mouth opening and are likely to improve the burning sensation in the mouth that is experienced by people who have oral submucous fibrosis.
What is oral submucous fibrosis?
Oral submucous fibrosis is a disease that causes increasing tightness of the cheeks and mouth. People with this condition often have persistent burning mouth pain. These problems can make eating, speaking and swallowing more difficult. Many medicines have been suggested to manage this condition and may be taken by mouth (systemically), applied locally to the surface (topically) or injected directly into the affected areas. Different forms of surgery or physiotherapy are also available.
What did we want to know?
We wanted to find out which treatments are effective for improving the symptoms of oral submucous fibrosis, and which treatments are the most effective. We also wanted to know what the risks and side effects of each treatment might be and how common these are.
What did we do?
We searched databases of medical and dental journals and research trials. We only selected trials known as randomised controlled trials. In this type of trial, participants are allocated to groups randomly. One group receives the intervention and the other receives a different treatment or no treatment at all. These trials aim to reduce the risk of introducing bias in clinical trials.
We wanted to focus on how well treatments worked to allow people with oral submucous fibrosis to return to normal eating, chewing and speaking. Because no trials looked at these measures, we chose increase in mouth opening (measured in millimetres between the upper and lower front teeth) and reduction oral burning sensation (measured on a scale from 0 to 100) as the most likely measures to improve quality of life in people with oral submucous fibrosis. We looked for details of these measures immediately after treatment (up to three months), in the medium term (three to six months) and in the longer term (after six months). We also looked for information on any 'adverse effects' (negative side effects of the treatments).
What did we find?
We found 30 relevant trials. Most trials looked at different treatments that each worked differently. Many trials compared different types of treatments with each other. We decided that trials comparing one treatment against no active treatment were most important because we do not know which, if any, treatments actually work.
The results told us that antioxidant medicines (which scavenge and neutralise unstable particles that are naturally formed during metabolism or by exposure to environmental toxins) taken by mouth may improve mouth opening slightly for up to six months after treatment, but we are not sure that this lasts longer than six months. Antioxidants may also reduce burning sensation in the mouth for more than six months after treatment and we think this might be an important improvement for people with oral submucous fibrosis.
The evidence for other treatments that we looked at was very uncertain.
Only half of the trials reported side effects or other potentially harmful effects of the treatments, so it is difficult to say confidently how safe any of the treatments might be.
What are the limitations of the evidence?
We are moderately confident that antioxidants help in the treatment of oral submucous fibrosis, but have little confidence in the other evidence because many trials had design limitations.
How up to date is the search?
We searched for trials up to 5 September 2022.
We found moderate-certainty evidence that antioxidants administered systemically probably improve mouth opening slightly at three to six months and improve burning sensation VAS scores up to and beyond six months. We found only low/very low-certainty evidence for all other comparisons and outcomes. There was insufficient evidence to make an informed judgement about potential adverse effects associated with any of these treatments. There was insufficient evidence to support or refute the effectiveness of the other interventions tested.
High-quality, adequately powered intervention trials with a low risk of bias that compare biologically plausible treatments for OSF are needed. It is important that relevant participant-reported outcomes are evaluated.
Oral submucous fibrosis (OSF) is a chronic disease of the oral cavity that causes progressive constriction of the cheeks and mouth accompanied by severe pain and reduced mouth opening. OSF has a significant impact on eating and swallowing, affecting quality of life. There is an increased risk of oral malignancy in people with OSF. The main risk factor for OSF is areca nut chewing, and the mainstay of treatment has been behavioural interventions to support habit cessation. This review is an update of a version last published in 2008.
To evaluate the benefits and harms of interventions for the management of oral submucous fibrosis.
We used standard, extensive Cochrane search methods. The latest search date was 5 September 2022.
We considered randomised controlled trials (RCTs) of adults with a biopsy-confirmed diagnosis of OSF treated with systemic, locally delivered or topical drugs at any dosage, duration or delivery method compared against placebo or each other. We considered surgical procedures compared against other treatments or no active intervention. We also considered other interventions such as physiotherapy, ultrasound or alternative therapies.
We used standard Cochrane methods. Our primary outcomes were 1. participant-reported resumption of normal eating, chewing and speech; 2. change or improvement in maximal mouth opening (interincisal distance); 3. improvement in range of jaw movement; 4. change in severity of oral/mucosal burning pain/sensation; 5. adverse effects. Our secondary outcomes were 6. quality of life; 7. postoperative discomfort or pain as a result of the intervention; 8. participant satisfaction; 9. hospital admission; 10. direct costs of medication, hospital bed days and any associated inpatient costs for the surgical interventions. We used GRADE to assess certainty of evidence for each outcome.
We included 30 RCTs (2176 participants) in this updated review. We assessed one study at low risk of bias, five studies at unclear risk of bias and 24 studies at high risk of bias.
We found diverse interventions, which we categorised according to putative mechanism of action. We present below our main findings for the comparison 'any intervention compared with placebo or no active treatment' (though most trials included habit cessation for all participants). Results for head-to-head comparisons of active interventions are presented in full in the main review.
Any intervention versus placebo or no active treatment
Participant-reported resumption of normal eating, chewing and speech
No studies reported this outcome.
Interincisal distance
Antioxidants may increase mouth opening (indicated by interincisal distance (mm)) when measured at less than three months (mean difference (MD) 3.11 mm, 95% confidence interval (CI) 0.46 to 5.77; 2 studies, 520 participants; low-certainty evidence), and probably increase mouth opening slightly at three to six months (MD 8.83 mm, 95% CI 8.22 to 9.45; 3 studies, 620 participants; moderate-certainty evidence). Antioxidants may make no difference to interincisal distance at six-month follow-up or greater (MD −1.41 mm, 95% CI −5.74 to 2.92; 1 study, 90 participants; low-certainty evidence).
Pentoxifylline may increase mouth opening slightly (MD 1.80 mm, 95% CI 1.02 to 2.58; 1 study, 106 participants; low-certainty evidence).
However, it should be noted that these results are all less than 10 mm, which could be considered the minimal change that is meaningful to someone with oral submucous fibrosis.
The evidence was very uncertain for all other interventions compared to placebo or no active treatment (intralesional dexamethasone injections, pentoxifylline, hydrocortisone plus hyaluronidase, physiotherapy).
Burning sensation
Antioxidants probably reduce burning sensation visual analogue scale (VAS) scores at less than three months (MD −30.92 mm, 95% CI −31.57 to −30.27; 1 study, 400 participants; moderate-certainty evidence), at three to six months (MD −70.82 mm, 95% CI −94.39 to −47.25; 2 studies, 500 participants; moderate-certainty evidence) and at more than six months (MD −27.60 mm, 95% CI −36.21 to −18.99; 1 study, 90 participants; moderate-certainty evidence).
The evidence was very uncertain for the other interventions that were compared to placebo and measured burning sensation (intralesional dexamethasone, vasodilators).
Adverse effects
Fifteen studies reported adverse effects as an outcome. Six of these studies found no adverse effects. One study evaluating abdominal dermal fat graft reported serious adverse effects resulting in prolonged hospital stay for 3/30 participants. There were mild and transient general adverse effects to systemic drugs, such as dyspepsia, abdominal pain and bloating, gastritis and nausea, in studies evaluating vasodilators and antioxidants in particular.