What options can be considered to help women stop smoking?

Nicole is a 43 year old woman who just established with you for primary care. She has a history of bipolar 1 (currently in remission on lithium, with 1 prior psychiatric hospitalization for suicidality) and high blood pressure for which she takes amlodipine. On the BP log she brings in, there are occasional 140 systolics in the last few weeks. In reviewing contributors to the recent elevations in blood pressure, Nicole shares that she’s been smoking cigarettes off and on for the last decade. Initially, she only smoked with friends at parties or bars, but later, she started smoking cigarettes when she was stressed to help her calm down. In the last 3 years, she’s noticed that a pack of cigarettes lasts her 1-2 days. Nicole doesn’t like that she smokes: she hates the smell, is frustrated with the cost, and is worried about future health effects. Recently, a friend suggested a vape instead of going outside for a cigarette. 

Nicole asks you what can help her stop smoking and if vaping is an option. She is ready to quit, but not sure if she will be able to as she’s never tried to quit before. First, you agree with Nicole on the concerning health effects of tobacco in general, and specifically, that it’s having a negative effect on her life and getting in the way of her overall health goals. What can you suggest to Nicole to help her reach her goal of stopping smoking? 

There are 7 FDA-approved medication treatments for nicotine dependence or tobacco use disorder (TUD), 3 long-acting controller medications (varenicline, bupropion, and nicotine replacement therapy (NRT) patches) and 4 short-acting NRT options (lozenge, gum, nasal spray, inhaler). These are summarized in UCSF’s free Rx for Change curriculum that includes clinician and patient resources for smoking (and vaping) cessation and a very comprehensive table about TUD pharmacotherapy in their toolkit

Society guidelines and expert opinion recommend starting with a long-acting controller medication in combination with a short-acting NRT agent (Barua 2018, Leone 2020). Combination NRT (CNRT) of patches and lozenge or gum––since this is a controller + short-acting NRT regimen––is an option for initial med recs. Varenicline is the most effective of these options, with a number needed to treat (NNT) compared to placebo of 11, a NNT of 25 for one person to not smoke at 6 months using varenicline instead of a nicotine patch, and a NNT of 13 for abstinence from tobacco at 6 months when comparing varenicline and bupropion (Tonstad 2020, Leone 2020). Combining varenicline with nicotine patches is even more effective than varenicline alone (NNT of 10), and some experts recommend combining controller medications (i.e. varenicline + patches) as first-line treatment. 

An important nuance here is that women may respond differently to treatment options for TUD than men. Specifically, in the data available, women responded better to varenicline for tobacco cessation (as opposed to bupropion or CNRT) (McKee 2016). This difference may be due to adherence difficulties related to the patches’ side effects. Quick aside: one may be able to reduce vivid dreams or sleep-related issues by removing the patch overnight. Even more interesting is the emerging evidence suggesting that alpha2 adrenergic agonists like guanfacine may be helpful in promoting tobacco reduction due to its attenuation of stress-related cues for smoking (and normalization of dopamine signaling) in women in particular (Sandiego 2018). While guanfacine has not been approved by the FDA for TUD, there are ongoing studies evaluating the impact of gender and sex on medication effects and efficacy for tobacco cessation.

Some clinicians may be wary of using varenicline in a patient with significant mental health conditions. After all, there used to be a black-box warning about varenicline use in this population. In 2016, a large, randomized trial showed that patients taking varenicline did NOT have an increased risk for neuropsychiatric adverse eventscompared with patients taking bupropion or using nicotine patches for TUD (Anthenelli 2016). The same year, the FDA removed the black box warning from varenicline. Nicole has bipolar 1 disorder, and varenicline can be used to help her stop smoking. Bupropion, on the other hand, would be relatively contraindicated for Nicole because of the risk of precipitating mania or increased mood cycling in patients with bipolar disorder. When managing neuropsychiatric disorders in people who are trying to quit smoking, remember that smoking induces the CYP1A2 enzyme. If someone stops smoking, the doses of medications that are metabolized by CYP1A2 may need to be reduced, including clozapine, olanzapine, haloperidol, and ropinirole, among others.  

Returning to Nicole‘s question about vaping, the evidence is limited as vaping seems to be less effective than NRT and carries its own health risks. A 2024 NEJM paper by Auer and colleagues showed that participants who were offered counseling and free electronic cigarettes had a higher 6-month cigarette abstinence rate (28% abstinence) than the group offered counseling and a $50 voucher (most of whom reported using NRT; 16% abstinent). However, important to remember is that in this trial, while the proportion of participants quitting smoking was higher in the e-cigarette group (compared to the voucher and counseling group), the e-cig group (by the nature of their delivery method) used nicotine for longer than the voucher and counseling group. Moreover, we don’t know the long-term health effects of e-cigs. While there’s evidence that e-cigarettes help reduce smoking under controlled trial conditions, we need to take this with a grain of salt because the e-cigarette devices tested in clinical trials to date differ substantially from the high concentration nicotine salt products that currently dominate the US market (Diaz 2023). While all patients should be offered FDA-approved meds and referred for counseling, patients who prefer to use e-cigarettes to quit smoking should also have an e-cig quit date. Thankfully, the Rx for Change website has recommendations on how to use NRT for vaping cessation.

Putting this all together, I would recommend starting with varenicline for Nicole because it is the most effective controller medicine to help her achieve her goal to stop smoking. I would emphasize that varenicline is the mainstay of treatment, but also offer short-acting NRT (gum or lozenge) to help with cravings in the moment. I would recommend counseling in addition to pharmacotherapy. Counseling can help improve adherence and make a big difference in how over the counter products work. Specifically, I would encourage her to consider participating in tobacco cessation counseling, either in a clinic with her PCP, through California’s helpline (1-800-300-8086), or the free “Kick It” website, which includes coaching and texting programs given the combo of meds and counseling is best for smoking cessation. 

Nicole agrees to start with varenicline; we review that nausea tends to be a common side effect. She can either take the med after eating or with a full glass of water to help reduce this risk. If she develops problems with nausea, we can extend the titration period or increase the dose only after the nausea at the lower dose has resolved. If Nicole isn’t able to meet her goals (e.g. quit smoking in 3 months) with varenicline, we can increase the dose of varenicline to enhance the effect. A trial in JAMA this month randomized patients who were still smoking despite telephone counseling and standard doses of either varenicline or combination NRT to 1) continue current treatment, 2) take increased doses of their current medication, or 3) switch to the other controller medication (Cinciripini 2024). People who were smoking while taking varenicline 1mg BID were more likely to achieve abstinence when the varenicline dose was increased (to 3mg total: 1mg in AM, 2mg at bedtime or 1.5mg BID) than when they continued at varenicline 1mg BID or switched to combination NRT.

Key Points

  1. Assess where the patient is in their stages of change to reduce or stop tobacco use and offer long-acting controller medication plus short-acting agents to help them meet their goals.
  2. Prescribe varenicline as the first line, most effective controller medication, especially for women. Varenicline is no worse for patients with mental health problems than bupropion or NRT patches.
  3. Recognize that patients may be using electronic cigarettes with the intent to quit smoking, but we don’t have much evidence to support this approach as e-cigarettes are not FDA-approved for TUD and may prolong nicotine use.

References:

  1. The brains of experts Dr. Pam Ling and Dr. Maya Vijayaraghavan. Thank you for reviewing this Snap!
  2. https://rxforchange.ucsf.edu/implementation_toolkit.php 
  3. Anthenelli RM et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): A double-blind, randomised, placebo-controlled clinical trial. Lancet 2016 Apr 22; [e-pub]. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30272-0/abstract 
  4. Auer R, Schoeni A, Humair JP, Jacot-Sadowski I, Berlin I, Stuber MJ, Haller ML, Tango RC, Frei A, Strassmann A, Bruggmann P, Baty F, Brutsche M, Tal K, Baggio S, Jakob J, Sambiagio N, Hopf NB, Feller M, Rodondi N, Berthet A. Electronic Nicotine-Delivery Systems for Smoking Cessation. N Engl J Med. 2024 Feb 15;390(7):601-610. doi: 10.1056/NEJMoa2308815. PMID: 38354139. https://www.nejm.org/doi/full/10.1056/NEJMoa2308815 
  5. Barua RS, Rigotti NA, Benowitz NL, Cummings KM, Jazayeri MA, Morris PB, Ratchford EV, Sarna L, Stecker EC, Wiggins BS. 2018 ACC Expert Consensus Decision Pathway on Tobacco Cessation Treatment: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2018 Dec 25;72(25):3332-3365. doi: 10.1016/j.jacc.2018.10.027. Epub 2018 Dec 5. PMID: 30527452.
  6. Cinciripini PM, Green CE, Shete S, et al. Smoking Cessation After Initial Treatment Failure With Varenicline or Nicotine Replacement: A Randomized Clinical Trial. JAMA. Published online May 02, 2024. doi:10.1001/jama.2024.4183
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  8. Diaz MC, Silver NA, Bertrand A, et alBigger, stronger and cheaper: growth in e-cigarette market driven by disposable devices with more e-liquid, higher nicotine concentration and declining pricesTobacco Control Published Online First: 03 August 2023. doi: 10.1136/tc-2023-058033
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  10. McKee, S; Smith, P; Kaufman, M; Mazure, C; Weinberger, A. Sex Differences in Varenicline Efficacy for Smoking Cessation: A Meta-Analysis, Nicotine & Tobacco Research, Volume 18, Issue 5, May 2016, Pages 1002–1011, https://doi.org/10.1093/ntr/ntv207
  11. Peltier, M; McKee, S. The role of sex hormones in targeting stress-induced tobacco craving, stress-reactivity, and smoking with guanfacine among women who smoke, Addiction Neuroscience, Volume 7, 2023, 100084, ISSN 2772-3925, https://doi.org/10.1016/j.addicn.2023.100084.
  12. Sandiego CM, Matuskey D, Lavery M, McGovern E, Huang Y, Nabulsi N, Ropchan J, Picciotto MR, Morris ED, McKee SA, Cosgrove KP. The Effect of Treatment with Guanfacine, an Alpha2 Adrenergic Agonist, on Dopaminergic Tone in Tobacco Smokers: An [11C]FLB457 PET Study. Neuropsychopharmacology. 2018 Apr;43(5):1052-1058. doi: 10.1038/npp.2017.223. Epub 2017 Sep 25. PMID: 28944773; PMCID: PMC5854798.
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