Nicotine replacement therapy is commonly used for patients wishing to quit smoking. Nicotine replacement therapy (NRT) is available in a number of formats, gum, sublingual tablets, lozenges, inhalers, nasal sprays or patches, in various dosages on prescription or over the counter. Prescriptions are based on the patient’s smoking dependency and tapered over a period of time. Side effects of coughing, nausea, vomiting, headache with rare cases of cardiovascular and gastro- intestinal side effects. Oral side effects including dry mouth and throat, aphthous ulcers and sore mouth have been reported and may lead to discontinuation of NRT.
The aim of this review was to look for certainty of evidence on possible significant association between locally delivered NRT’s and related oral side effects.
Methods
A protocol for the review was registered with the Open Science Framework register. Searches were conducted in the Medline/PubMed, the Cochrane Central Register of Clinical Trials (CENTRAL) and the Database of Abstracts of Reviews of Effects (DARE). Randomised controlled trials (RCTs) in adults wishing to quit smoking and prescribed locally delivered NRT as chewing gums, sublingual tablet, lozenges, transdermal patches, nasal sprays or inhalers published in English were considered. 3 reviewers independently extracted data and assessed risk of bias using the Cochrane tool . Mean difference and odds ratio with 95% confidence intervals (CI) were used for the effect estimates. The GRADE approach was used to assess the certainty of the evidence.
Results
- 28 RCTs were included.
- No studies were considered to be at low risk of bias, 24 were considered to be at high risk of bias and 4 at medium risk.
- Oral or aphthous ulcers were reported in 7 studies (1809 patients,930 NRT,879 controls). Overall, there was no statistically significant occurrence of ulcers with NRT use but a significant increase in odds with 4mg gum (see table below)
| No. of studies | Odds Ratio (95%CI) | |
| 2mg nicotine gum | 4 | 2.01 (0.79 to 5.13) |
| 4mg nicotine gum | 3 | 5.23 [1.02 to 26.89) |
| 2mg nicotine sublingual tablet | 1 | 1.07 (0.56 to 2.01) |
| Nicotine patch | 1 | 1.20 (0.35 to 4.10) |
| Overall | 7 | 1.60 (0.94 to 2.73) |
- 9 studies (2476 patients, 1387 NRT,1098 controls) reported mouth or throat irritation. Overall, a statistically significant number of patients using NRT developed mouth or throat irritation as did those using a nicotine inhaler (see table below)
| No. of studies | Odds Ratio (95%CI) | |
| Nicotine inhaler | 2 | 3.41 (2.05 to 5.67) |
| Nicotine nasal spray | 4 | 2.53 (0.73 to 8.78) |
| 2mg nicotine sublingual tablet | 1 | 14.55 (0.75 to 283.37) |
| 2mg nicotine gum | 2 | 1.45 (0.83 to 2.50) |
| Overall | 9 | 2.54 (1.23 to 5.25) |
- Gastric reflux or vomiting was reported in 9 studies (3552 patients, 1791 NRT, 1761 controls). Overall, a statistically significant number of patients using NRT reported gastric reflux and vomiting as did those using 4mg nicotine gum (see table below)
| No. of studies | Odds Ratio (95%CI) | |
| Nicotine patch | 4 | 1.41 (0.86 to 2.28) |
| Nicotine nasal spray | 2 | 2.24 (0.91 to 5.53) |
| 2mg nicotine gum | 2 | 2.12 (0.59 to 7.37) |
| 4mg nicotine gum | 2 | 4.97 (1.54 to 16.02) |
| 4mg nicotine lozenge | 1 | 16.49 (2.15 to 126.69) |
| Overall | 9 | 1.97 (1.34 to 2.90) |
- 6 studies (2574 patients, 1366 NRT, 1208 controls) reported on oral dryness with pooled estimates showing no different between NRT and controls OR = 0.77 (95%CI: 0.51 to 1.16)
- Oral soreness was reported in 7 studies (1660 patients, 861 NRT, 799 controls). A significant number of patients developed oral soreness with 2 mg or 4 mg nicotine gum, nicotine inhaler or nicotine patch (see table below)
| No. of studies | Odds Ratio (95%CI) | |
| 4mg nicotine gum | 4 | 2.84 (1.06 to 7.62) |
| 2mg nicotine gum | 2 | 3.28 (0.30 to 35.69) |
| Nicotine inhaler | 1 | 1.67 (0.91 to 3.07) |
| Nicotine patch | 4 | 3.43 (1.46 to 8.06) |
| Overall | 7 | 2.22 (1.40 to 3.55) |
- The GRADE certainty of evidence was considered to be low for mouth or throat irritation and moderate for other outcomes.
Conclusions
The authors concluded: –
It is important to understand that significant implications are caused due to NRT, on oral health. All patients on NRT must adhere to their regular dentist visits and must check their oral mucosa before initiating NRT.
Comments
The reviewers published their protocol on the Open Science Framework register and searched 3 major databases. However restricting inclusion to English language papers may have excluded some relevant studies. While 28 RCTs were included 24 were considered to be at high risk of bias mainly due to concerns over allocation concealment. Overall, the review indicates that a significant number of patients reported oral side effects including oral soreness, gastric reflux or vomiting, and mouth or throat irritation, with the largest number of events being reported for mouth or throat irritation. The studies used a range of NRT products and dosages and while sub-analyses were presented for these the number of events for some adverse events was low so these should be considered cautiously. The review authors suggest that future studies should specifically ask about oral adverse effects. The dental team are in a good position to encourage patients using tobacco patients to quit and there is evidence that quit rates increase when dental professionals offer behavioural support to promote tobacco cessation (Dental Elf – 1st Mar 2021).
Links
Primary Paper
Sivaramakrishnan G, Alsobaiei M, Sridharan K. Oral side effects of locally delivered nicotine replacement therapy: A meta-analysis of randomized controlled trials. Int J Dent Hyg. 2022 Apr 29. doi: 10.1111/idh.12594. Epub ahead of print. PMID: 35485245.
Protocol for review in the Open Science Framework register
Other references
Dental Elf – 1st Mar 2021
