NRT does not deliver nicotine as rapidly as a cigarette, and nicotine blood concentrations obtained from other tobacco products (i.e., smokeless tobacco, cigars or pipes) is higher than can be achieved from NRT at standard doses. Initial smoking abstinence is often not achieved with NRT due to, in part, to inadequate nicotine “replacement” (i.e., achievement of venous nicotine concentrations with NRT comparable to those achieved when using tobacco ad lib
As a consequence, tobacco users who achieve initial tobacco abstinence with NRT have an increased risk for relapse due to cravings and withdrawal that are inadequately treated as a consequence of nicotine under-replacement. However, the effect may not all be related to the higher serum nicotine concentrations achieved. For example, studies of higher dose nicotine patch therapy have not consistently demonstrated increased tobacco abstinence rates compared to standard dose patch therapy.
Instead, efficacy may be related to the timing or form in which the NRT is delivered
The two types of combination NRT that have been described are sequential and concurrent. Sequential therapy can theoretically provide initial stable nicotine dosing to achieve abstinence (i.e., nicotine patch) and then intermittent ad lib
dosing to prevent relapse.
However, little data exists to support sequential therapy.
Relatively more data exists regarding the simultaneous use of multiple NRTs (i.e., concurrent therapy). Concurrent NRT therapy allows for the delivery of nicotine passively with long-acting NRT (i.e., nicotine patch) and for the active ad lib
administration of short-acting NRT (i.e., gum, lozenge, inhaler, and nasal spray). This combination provides the advantages of higher treatment adherence with the nicotine patch
and the empowering of smokers to deal with acute cravings and withdrawal symptoms through self-administration of short-acting NRT. Combination NRT also provides the opportunity to achieve higher serum nicotine concentrations which may
translate into improved treatment efficacy and withdrawal symptom relief and, ultimately, improved treatment efficacy. Despite the inclusion of combination pharmacotherapy in the 2008 USPHS Guidelines, many clinicians and pharmacists are reluctant to recommend or prescribe doses that are not recommended on product labels.
Studies evaluating the combination of the nicotine patch + nicotine gum have demonstrated that the combination is superior to monotherapy for increasing smoking abstinence rates at
and 24 weeks.
Combination therapy is also associated with higher salivary cotinine concentrations and lower withdrawal scores.
Combination therapy with the nicotine patch + nasal spray has been investigated. In an open-label trial of 1384 smokers randomized to nicotine patch therapy + nasal spray or either therapy alone, combination therapy was associated with significantly higher smoking abstinence rates at 6 weeks compared with either monotherapy.
In a placebo-controlled clinical trial, 237 subjects were randomized to the 15 mg nicotine patch with tapering for 5 months + nasal spray for up to 1 year or the nicotine patch + placebo. The nicotine patch + nicotine nasal spray was superior to nicotine patch + placebo nasal spray at both short (6 weeks & 3 months) and long-term (12 months) follow-up.
Combination therapy with the nicotine patch + inhaler has also been investigated. In a placebo-controlled randomized trial, 400 subjects were randomized to the 15 mg/16 hour nicotine patch + nicotine inhaler (group 1) or placebo patch + nicotine inhaler (group 2).
Significantly higher smoking abstinence rates were observed with the nicotine patch + inhaler at 6 and 12 weeks compared to the inhaler alone. Combination therapy was also associated with higher levels of nicotine replacement and with less tobacco withdrawal.
In a large effectiveness study in the primary care setting, 1346 patients were randomized to bupropion SR, lozenge, patch, patch + lozenge, or bupropion SR + lozenge.
The nicotine patch + lozenge was observed to be superior to patch monotherapy.
In a systematic review of NRT for stopping smoking, seven studies including over 3200 subjects evaluating combination NRT were identified. Combination NRT significantly increased long-term (≥ 6 months) smoking abstinence rates compared to single NRT or no NRT (Risk ratio 1.35; 95% CI: 1.11-1.63).
The strength of this effect was similar when removing the study with the no-NRT control condition.
5.2. Safety & Tolerability
In general, combination NRT is well-tolerated and side effects are consistent with the anticipated side effects of each agent alone. Specifically, studies have not observed an increase risk of nicotine toxicity with combination therapy.