Ninety-two RCTs (n=32,185 patients, treatment groups size ranged from three to 716 ) and 28 observational studies (n=145,205 patients, range 22 to 65,599) were included. Thirty-eight RCTs reported sequence generation, 17 reported allocation concealment and 81 reported patient blinding. Patients did not have to pay for nicotine replacement therapy in any of the studies.
RCTs: Nicotine replacement therapy was associated with a statistically significant increase in heart palpitations and chest pain (OR 2.06, 95% CI 1.51 to 2.82; 12 RCTs), nausea or vomiting (OR 1.67, 95% CI 1.37 to 2.04; 31 RCTs), gastrointestinal complaints (OR 1.54, 95% CI 1.25 to 1.89; 26 RCTs) and insomnia (OR 1.42, 95% CI 1.21 to 1.66; 19 RCTs). Significant heterogeneity was found for nausea or vomiting (I2=62%; a large amount of heterogeneity was explained by route of nicotine replacement therapy delivery and allocation concealment) and insomnia (I2=65%; heterogeneity was explained by trial duration). There was no statistically significant difference between nicotine replacement therapy and control in anxiety or depressive symptoms.
The nicotine replacement therapy patch was associated with a statistically significant increase in skin irritations (OR 2.80, 95% CI 2.28 to 3.24; 32 RCTs).
Orally administered nicotine replacement therapy was associated with a statistically significant increase in mouth and throat soreness (OR 1.87, 95% CI 1.36 to 2.57; 23 RCTs), mouth ulcers (OR 1.49, 95% CI 1.05 to 2.20; six RCTs), hiccups (OR 7.68, 95% CI 4.59 to 12.85; 14 RCTs) and coughing (OR 2.89, 95% CI 1.92 to 4.33; 12 RCTs). Significant heterogeneity was found for mouth and throat soreness (I2=66%) and coughing (I2=72%).
Observational studies: The most common adverse events were skin irritation (19.5%; 16 studies) and insomnia (11.4%; 18 studies).