09:24 AM

504 - Nicotine Replacement Therapy, Sleep Apnea, Stretching More

Take 3 – Practical Practice Pointers©

From the Cochrane Database of Systematic Reviews

1)  Becoming More Nuanced with Nicotine Replacement Therapy


Tobacco smoking is the leading cause of preventable disease, disability, and death in the United States and costs billions of dollars in direct medical costs each year.  Although considerable progress has been made in reducing cigarette smoking over the past 3 decades, in 2018, 13.7% of U.S. adults (34.2 million people) were still current cigarette smokers (compared with 23.3% in 2000).  The 2015 USPSTF recommends that clinicians ask all adults about tobacco use, advise them to stop using tobacco, and provide behavioral interventions and U.S. Food and Drug Administration–approved pharmacotherapy for cessation to adults who use tobacco. (A recommendation)  There are presently 5 forms of nicotine replacement therapy (NRT) and 2 additional medications, bupropion and varenicline, that are FDA approved for smoking cessation. 

Although there is high-certainty evidence that NRT is effective for achieving long-term smoking abstinence, it is unclear whether different forms, doses, durations of treatment or timing of use impacts its effects.  The Cochrane Database of Systematic Reviews recently published a review synthesizing the evidence to clarify these questions.  The review included randomized trials in people motivated to quit, comparing one type of NRT use with another.  The reviewers excluded studies that did not assess cessation as an outcome, with follow-up of fewer than six months, and with additional intervention components not matched between arms.

The reviewers identified 40 studies which met the review criteria and were judged to be at low risk for bias.  They concluded that there is high-certainty evidence that using combination NRT versus single-form NRT and 4 mg versus 2 mg nicotine gum can result in an increase in the chances of successfully stopping smoking. Due to imprecision, evidence was of moderate certainty for patch dose comparisons. There is some indication that the lower-dose nicotine patches and gum may be less effective than higher-dose products. Using a fast-acting form of NRT, such as gum or lozenge, resulted in similar quit rates to nicotine patches. There is moderate-certainty evidence that using NRT before quitting may improve quit rates versus using it from quit date only.  Evidence for the comparative safety and tolerability of different types of NRT use is limited.  Cardiac adverse events (AEs), serious adverse events SAEs and withdrawals due to treatment were all measured variably and infrequently across studies, resulting in low- or very low-certainty evidence for all comparisons. Most comparisons found no clear evidence of an effect on these outcomes, and rates were low overall.

Mark’s Comments:

One conclusion that is clear across multiple reviews and guidelines is that combination therapy is more effective that single therapy.  I found it interesting that this review did not include inhaled NRT.  Our April 24, 2023 Take 3 reviewed another Cochrane Database Review looking at whether electronic cigarettes be used for smoking cessation and concluded that found high-certainty evidence from six studies that e-cigs achieved greater quit rates than nicotine replacement therapy (NNT = 25 over 6-12 months).   This becomes important as according to a 2022 Gallup poll, 8% of US adults had used e-cigarettes in the past week.  However, it appears we may be simply substituting one addiction for another.  The 2022 National Youth Tobacco Survey indicated that 16.5% of US high school students had used tobacco products (9.4% e-cigarettes) in the past 30 days.  Given the health hazards of all these products, it is imperative that we don’t become “resigned” that the challenge is too big to overcome.  We owe it to those we care for, and care about.

The 3rd reference, “Tips from Former Smokers” is a wonderful resource from the CDC and includes much helpful patient information.  It would be worth sharing with patients who are “ready” to quit but haven’t taken the next step. 


·         Theodoulou A, Chepkin SC, Ye W, Fanshawe TR, et al.  Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews 2023, Issue 6. June 2023.  Art. No.: CD013308.  Link

·         US Department of Health and Human Services.  Smoking Cessation:  A Report of the Surgeon General.  Executive Summary. 2020.  Link

·         CDC.  Tips From Former Smokers:  Five New Ways to Quit with Medications.  Last reviewed 28 November 2022.  Link


From the Technology Assessment Program of the AHRQ

2)  Sleep Apnea and Long-term Outcomes


Over the past 20 years, the diagnosis and management of obstructive sleep apnea (OSA) has become somewhat of an institution. Family physicians can get a Certificate of Added Qualifications (CAQ) in sleep medicine. We see it underlying cases of chronic fatigue, hypertension, and lower extremity edema. And we have seen a rapid expansion of the technological aspects of the diagnosis and treatment of sleep apnea. Certainly, with the rising prevalence of obesity in the United States - a well-defined risk factor for sleep apnea - this condition merits serious consideration.

A health technology assessment performed by the Brown Evidence-based Practice Center (EPC) for the US Agency for Healthcare Research and Quality (AHRQ) reviews the evidence behind diagnostic and therapeutic approaches to obstructive sleep apnea, with a focus on long-term outcomes. The EPC updated a 2011 report on OSA with a comprehensive search of multiple databases looking for high quality randomized and non-randomized studies of continuous positive airway pressure (CPAP) as well as studies of the Apnea-Hypopnea Index (AHI) used to evaluate OSA all with an eye toward important health outcomes for sleep apnea. They specifically eschewed intermediate outcomes such as sleepiness.

Fifty-two studies were found and analyzed. The first striking finding of the review was the included studies’ complete lack of consistency in the apnea and hypopnea criteria used to diagnose and treat OSA. Second, the RCTs of CPAP use did not find any effect on mortality, cardiovascular mortality, stroke, myocardial infarction (MI), or combinations of those outcomes. The combined results of the non-randomized studies did demonstrate a reduction in overall mortality, and the combined results of randomized and non-randomized studies showed a moderate reduction in overall mortality (a effect size (ES) of 0.61 (95% CI 0.49 to 0.76)). Curiously, however, the combined studies were unable to find differences in any of the disease outcomes (transient ischemic attack, angina, coronary artery revascularization, congestive heart failure, and atrial fibrillation). Furthermore, CPAP did not result in differences in driving accidents, quality of life measurements, cognitive function, mental health symptoms, sexual function, or workdays missed. Multiple attempts at slicing the sample by different patient characteristics did not reveal a subgroup that benefitted. Adverse event data was sparse and not well-collected; most of it was from reports of difficulty with the equipment (poor humidification, etc.). There were few useful data on mandibular advancement devices. Finally, the study found no data correlating improvement in AHI and any improvement in clinical outcomes.

The authors call primarily for long-term studies of CPAP use examining patient-oriented outcomes (i.e., not simply breathing measures like AHI or short-term symptoms like sleepiness). But it is clear from the review that the whole area requires better quality evidence.

John’s Comments:

Well, this is discouraging. While I have seen enough of this condition in practice to take it seriously, it seems we are establishing rules and guidelines (like CPAP-usage monitoring and screening for OSA prior to surgery) that lack a foundation in patient-oriented evidence. For such a prevalent and costly condition, one would think the demand for good quality evidence would be stronger. It is worth noting that the Centers for Medicare and Medicaid Services actually requested this review from AHRQ, so maybe they can drive the development of better research data.


·         Balk EM, Adam GP, Cao W, et al. Long-Term Health Outcomes in Obstructive Sleep Apnea: A Systematic Review of Comparative Studies Evaluating Positive Airway Pressure and the Validity of Breathing Measures as Surrogate Outcomes. Agency for Healthcare Research and Quality; 2022:182. Link

From PeerRxMed ( www.PeerRxMed.org )

3)  Time For Us All to Stretch More


“Courage starts with showing up and letting ourselves be seen ….”  Brene Brown

It had finally happened!  Four years ago, a decade after the vision for PeerRxMed had been planted in me, the first pilot was started with 40 participants.  Eight months later, after a successful pilot and with refinements in place, I hit the “make public” button on the PeerRxMed website and it was officially “out there.”  I had no idea when I clicked that button that 2 weeks later the World Health Organization would declare the coronavirus outbreak a global pandemic, changing our lives forever and making the need for peer connection even more pressing.  

As excited as I was to share the program and process with colleagues across the country, I was equally surprised as to how hard it was for me to do this.  The vulnerability I felt in sharing this dream more widely was quite real (that’s why it took 10 years to start it), and my fears that it wouldn’t be “perfect”, or some might think it was “soft” or “trite” and the potential criticism that may arise almost prevented me from moving ahead.  What I also didn’t anticipate was how emotionally challenging it would be for me, week after week, to continue to hit “send” on my weekly messages as I shared my thoughts, ideas, reflections and feelings with the expectation that I too would be connecting with my PeerRx buddies around these things. 

Despite my initial and ongoing hesitations, I'm so glad I have made the decision to "show up" in my greater fullness and let more of my authentic self be seen over these past 4 years in the presence of a like-minded community of colleagues.  As Brene Brown indicates (and has built a career upon), many of us don’t allow wonderful, deeply important parts of ourselves to be “seen” due to our fear as to how those parts will be received.   It is often our shame and fear and vulnerability that also hold us back from bringing our most important Gifts to the world.   If that is true for you, her antidote is a life-giving concoction of self-compassion and courage and connection.  

It occurs to me that perhaps you’ve also experienced this same vulnerability week-by-week as you’ve connected with your PeerRx partner.  Thank you for sharing that journey.  And now I’m going to “stretch” myself again and muster up the courage to make 2 requests of you.  First, I’m inviting you to “stretch” with me by inviting 3 of your colleagues to find a buddy and join the adventure of connection and encouragement that is PeerRx.   Second, next week I’ll be sending out a link for the first ever PeerRxMed survey, and I need your input as to what the evolution of this process and platform might look like.

I believe that participation in PeerRxMed can help each of us find the “voice” that is our better self and help us release our even greater Gifts to the world.  And the world could sure use multiple doses of “better selves” and “greater Gifts” right now.  So, thanks in advance for having the courage to invite your authentic and imperfect self to show up more this week and beyond, and for inviting others to do the same.  You’ll be a better you because of it, and so will they.  

Remember, no one should care alone ….


Mark and John

Carilion Clinic Department of Family and Community Medicine

Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.

Email: mhgreenawald@carilionclinic.org