**High-Dose Nicotine Patch Therapy and Combination Nicotine Replacement
Therapy**

Prepared by Dr. Timothy Carmody, San Francisco VA Medical Center

**[High-Dose Nicotine Patch Therapy (NPT)]{.underline}**

**What is "High-Dose" Nicotine Patch Therapy (NPT)?**

-   High-dose NPT involves using multiple nicotine patches to
    individualize and maximize the level of nicotine replacement,
    providing a constant concentration in the body, to improve control
    of withdrawal symptoms.

**What is the rationale for High-Dose NPT?**

-   Many patients are underdosed at standard nicotine patch doses. The
    rationale for high-dose NPT is to provide more complete replacement
    of blood nicotine levels to control withdrawal symptoms during early
    cessation of cigarette smoking (Benowitz et al, 1998).

-   Individualizing the nicotine patch dose is warranted because of the
    baseline intra-individual variability in nicotine and cotinine
    concentrations among smokers who smoke a similar number of
    cigarettes per day (Sachs & Benowitz, 1996).

-   At standard doses, none of the current NRT formulations achieve
    nicotine levels like those seen during typical smoking and
    tolerability as high as 63mg of nicotine has been demonstrated
    (Zevin 1998).

**What is the effectiveness of High-Dose NPT?**

-   High-dose NPT has been shown to be safe and well tolerated in
    patients who smoke more than 20 cigarettes per day (Dale et al,
    1995; Fredrickson et al, 1995).

-   High-dose NPT may be particularly appropriate and helpful for heavy
    smokers who have failed single-dose patch therapy (Dale et al, 1995;
    Hughes, 1995).

-   Clinical trials examining the efficacy of high-dose patch therapy
    have produced mixed results (Fiore et al, 2000; Jorenby et al, 1995;
    Tonnesen et al, 1999). Although modest to substantial benefits with
    nicotine patch increases up to 25mg and 44mg, respectively, have
    been reported, other published data indicate no incremental benefit
    with doses between 21 to 42mg.

**What are the dosing guidelines for High-Dose NPT?**

-   Hurt et al (2003) have developed guidelines for implementing and
    tailoring high-dose NPT. (Would suggest including abbreviated dosing
    guidelines here or in an appendix to this document or listing a
    website where the guidelines can be found for reference. -- This
    statement as written doesn't answer the question it asks i.e. what
    are the dosing guidelines for high-dose NPT?)

**What cautions need to be taken when considering use of High-Dose
NPT?**

-   Higher doses of nicotine patch can increase the production of and
    response to nitric oxide in the bypass grafts in patients who have
    had coronary artery bypass surgery, producing vasodilation (Clouse
    et al, 2000). High dose NPT should be used with caution in pregnant
    women, in patients with coronary artery disease within two weeks
    post MI, and those with serious or worsening angina pectoris.

**[Bottom line:]{.underline}** While there is a clear rationale for
high-dose NPT, evidence for its efficacy has been mixed. If a provider
and health care facility choose to use it, the most appropriate patients
for high-dose NPT are heavy smokers who have already failed approved
first-line therapies.

**[Combination Nicotine Replacement Therapy (CNRT)]{.underline}**

**What is Combination Nicotine Replacement Therapy (CNRT)?**

-   CNRT involves the use of nicotine patches to provide a constant
    concentration of nicotine in combination with another faster-acting
    form of NRT (gum, lozenges, inhaler, or nasal spray) to relieve
    breakthrough cravings and withdrawal symptoms.

**What is the rationale for CNRT?**

-   The rationale for combination NRT is that smokers may need the
    combination of a slow delivery system to achieve a constant
    concentration of nicotine to relieve cravings and nicotine
    withdrawal symptoms and a faster-acting preparation that can relieve
    breakthrough cravings and withdrawal symptoms.

**What is the effectiveness of CNRT?**

-   The empirical support for combination NRT is much more extensive and
    appears to be of greater benefit than that for high-dose NPT (Silagy
    et al, 2002). Four of the five published studies that have examined
    the efficacy of combination NRT have tested the combination of
    nicotine patches and nicotine gum and found that this combination
    provides incremental efficacy compared with either product alone.
    Although less information is available on other CNRT, the
    combination of the nicotine patch and nasal spray has also shown
    clinical benefit in increasing long term abstinence rates over a
    single form of NRT (Blondal 1999). At this time, no published study
    has tested the efficacy of other NRT combinations.

-   The PHS clinical practice guidelines (Fiore et al, 2000) issued a B
    level of support for some NRT combinations, including (name which
    ones). This level of endorsement implies that evidence for such use
    is suggestive but not definitive. The guidelines indicate that
    patients should be encouraged to use combination NRT if they are
    unable to quit using a single type of first-line pharmacotherapy.

-   Clinical trials examining the efficacy of high-dose NPT have
    produced conflicting results, supporting the notion that the
    improved success produced by combination nicotine medications may
    depend on the use of two distinct delivery systems: a steady-state
    delivery system and a self-administered, faster acting system.
    However, it is unclear whether the apparent superiority of
    combination therapy is due to the sensory effects provided by
    multiple types of delivery systems, to a greater percentage of
    nicotine substitution resulting from the higher blood nicotine
    concentrations, to the additional acute blood concentration
    increases provided by the faster-acting formulation, or to some
    combination of these and other factors.

**What are the dosing guidelines for CNRT?**

-   Specific guidance regarding dosing of CNRT remains to be clarified,
    for example, the recommended number of pieces of nicotine gum while
    also wearing the patch. Empirically-based dose instructions for
    combination NRT need to be developed to maximize the benefits and
    minimize the risks.

-   Experts have suggested the following dosing guidelines (currently
    not included in product labeling): Dose the patch as described.
    Prescribe any of the other NRT products on an as needed basis when
    acute withdrawal symptoms and urges to use tobacco occur. Adjust
    dose of patch if frequent use of other NRT: goal is to minimize need
    for active dosing.

**What cautions need to be taken when considering use of CNRT?**

-   Combination NRT should be used with caution with pregnant women and
    individuals with cardiovascular disease within two weeks post-MI, or
    with serious or worsening angina pectoris.

**References:**

Benowitz, N.L., Zevin, S., & Jacob, P. (1998). Suppression of nicotine
intake during *ad libitum* cigarette smoking by high-dose transdermal
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Blondal T, Gudmundsson LJ, Olafsdottir I, Gustavsson G, Westin A.
Nicotine nasal spray with nicotine patch for smoking cessation:
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Clouse, W.D., Yamaguchi, H., Phillips, M.R., Hurt, R.D. et al (2001).
Effects of transdermal nicotine treatment on structure and function of
coronary artery bypass grafts. *Journal of Applied Physiology, 89*,
1213-1223.

Dale, R.C., Hurt, R.D., Offord, K.P. et al (1995). High-dose nicotine
patch therapy: Percentage of replacement and smoking cessation. *JAMA,
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Fiore, M.C., Bailey, W.C., Cohen, S.J. et al. (2000). *Treating Tobacco
Use and Dependence (Clinical Practice Guideline)*. Rockville, MD: U.S.
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Fredrickson, P.A. et al (1995). High dose transdermal nicotine therapy
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Hughes, J.R. (1995). Treatment of nicotine dependence: is more better?
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Hughes, J.R., Lesms, G.R., Hatsukami, D.K. et al (1999). Are higher
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Hurt, R.D., Ebbert, J.O., Hays, J.T., & Dale, L.C. (2003). Pharmacologic
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Jorenby, D.E., Smith, S.S., Fiore, M.C., Hurt, R.D. et al (1995).
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Sachs, D.P.L., & Benowitz, N.L. (1996). Individualizing medical
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Silagy, C., Lancaster, T., et al (2002). Nicotine replacement therapy
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Sweeney, C.T., Fant, R.V., Fagerstrom, K.O., McGovern, J.F., &
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Tonnesen, P., Paoletti, P., Gustavsson, G., Russell, M.A. et al (1999).
Higher dosage nicotine patches increase one-year smoking cessation
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Zevin S, Jacob IIIP, Benowitz NL. Dose-related cardiovascular and
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