Skip to main content Accessibility help

Sleep Disturbance During Smoking Cessation: Withdrawal or Side Effect of Treatment?

  • Rebecca L. Ashare (a1), Caryn Lerman (a2), Rachel F. Tyndale (a3) (a4), Larry W. Hawk (a5), Tony P. George (a3), Paul Cinciripini (a6) and Robert A. Schnoll (a2)...


Introduction: The nicotine–metabolite ratio (NMR) predicts treatment response and is related to treatment side effect severity. Sleep disturbance may be one important side effect, but understanding sleep disturbance effects on smoking cessation is complicated by the fact that nicotine withdrawal also produces sleep disturbance.

Aims: To evaluate the effects of withdrawal and treatment side effects on sleep disturbance.

Methods: This is a secondary analysis of data from a clinical trial (Lerman et al., 2015) of 1,136 smokers randomised to placebo (n = 363), transdermal nicotine (TN; n = 381), or varenicline (n = 392) and stratified based on NMR (559 slow metabolisers; 577 normal metabolisers). Sleep disturbance was assessed at baseline and at 1-week following the target quit date (TQD). We also examined whether sleep disturbance predicted 7-day point-prevalence abstinence at end-of-treatment (EOT).

Results: The varenicline and TN groups exhibited greater increases in sleep disturbance (vs. placebo; treatment × time interaction; p = 0.005), particularly among those who quit smoking at 1-week post-TQD. There was a main effect of NMR (p = 0.04), but no interactions with treatment. TN and varenicline attenuated withdrawal symptoms unrelated to sleep (vs. placebo). Greater baseline sleep disturbance predicted relapse at EOT (p = 0.004).

Conclusions: Existing treatments may not mitigate withdrawal-related sleep disturbance and adjunctive treatments that target sleep disturbance may improve abstinence rates.


Corresponding author

Address for correspondence: Rebecca Ashare, PhD, Department of Psychiatry and Abramson Cancer Center, University of Pennsylvania, 3535 Market Street, 4th Floor, Philadelphia, PA 19104, USA. Email:


Hide All
Ashare, R. L., Wileyto, E. P., Perkins, K. A., & Schnoll, R. A. (2013). The first 7 days of a quit attempt predicts relapse: Validation of a measure for screening medications for nicotine dependence. J Addict Med, 7 (4), 249254.
Augustson, E. M., Wanke, K. L., Rogers, S., Bergen, A. W., Chatterjee, N., Synder, K. et al. (2008). Predictors of sustained smoking cessation: A prospective analysis of chronic smokers from the alpha-tocopherol Beta-carotene cancer prevention study. American Journal of Public Health, 98 (3), 549555.
Boutou, A. K., Tsiata, E. A., Pataka, A., Kontou, P. K., Pitsiou, G. G., & Argyropoulou, P. (2008). Smoking cessation in clinical practice: Predictors of six-month continuous abstinence in a sample of Greek smokers. Prim Care Respir J, 17 (1), 3238.
Brown, R. A., Burgess, E. S., Sales, S. D., Whiteley, J. A., Evans, D. M., & Miller, I. W. (1998). Reliability and validity of a smoking timeline follow-back interview. Psychology of Addictive Behaviors, 12 (2), 101112.
Buysse, D. J., Ancoli-Israel, S., Edinger, J. D., Lichstein, K. L., & Morin, C. M. (2006). Recommendations for a standard research assessment of insomnia. Sleep, 29 (9), 11551173.
Buysse, D. J., Reynolds, C. F. 3rd, Monk, T. H., Berman, S. R., & Kupfer, D. J. (1989). The pittsburgh sleep quality index: A new instrument for psychiatric practice and research. Psychiatry Res, 28 (2), 193213.
Chenoweth, M. J., Novalen, M., Hawk, L. W., Schnoll, R. A., George, T. P., Cinciripini, P. M. et al. (2014). Known and novel sources of variability in the Nicotine metabolite ratio in a large sample of treatment-seeking smokers. Cancer Epidemiology Biomarkers & Prevention, 23 (9), 17731782.
Colrain, I. M., Trinder, J., & Swan, G. E. (2004). The impact of smoking cessation on objective and subjective markers of sleep: Review, synthesis, and recommendations. Nicotine & Tobacco Research, 6 (6), 913925.
Faessel, H. M., Obach, R. S., Rollema, H., Ravva, P., Williams, K. E., & Burstein, A. H. (2010). A review of the clinical pharmacokinetics and pharmacodynamics of varenicline for smoking cessation. Clin Pharmacokinet, 49 (12), 799816.
Ferguson, S. G., Shiffman, S., & Gwaltney, C. J. (2006). Does reducing withdrawal severity mediate nicotine patch efficacy? A randomized clinical trial. J Consult Clin Psychol, 74 (6), 11531161.
Foulds, J., Russ, C., Yu, C. R., Zou, K. H., Galaznik, A., Franzon, M. et al. (2013). Effect of varenicline on individual nicotine withdrawal symptoms: A combined analysis of eight randomized, placebo-controlled trials. Nicotine Tob Res, 15 (11), 18491857.
Fredrickson, P. A., Hurt, R. D., Lee, G. M., Wingender, L., Croghan, I. T., Lauger, G. et al. (1995). High dose transdermal nicotine therapy for heavy smokers: Safety, tolerability and measurement of nicotine and cotinine levels. Psychopharmacology (Berl), 122 (3), 215222.
Fucito, L. M., Redeker, N. S., Ball, S. A., Toll, B. A., Ikomi, J. T., & Carroll, K. M. (2014). Integrating a behavioural sleep intervention into smoking cessation treatment for smokers with insomnia: A randomised pilot study. J Smok Cessat, 9 (1), 3138.
Garvey, A. J., Bliss, R. E., Hitchcock, J. L., Heinold, J. W., & Rosner, B. (1992). Predictors of smoking relapse among self-quitters: A report from the Normative aging study. Addict Behav, 17 (4), 367377.
Gonzales, D., Rennard, S. I., Nides, M., Oncken, C., Azoulay, S., Billing, C. B. et al. (2006). Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: A randomized controlled trial. JAMA, 296 (1), 4755.
Gourlay, S. G., Forbes, A., Marriner, T., Pethica, D., & McNeil, J. J. (1995). Double blind trial of repeated treatment with transdermal nicotine for relapsed smokers. BMJ, 311 (7001), 363366.
Heatherton, T. F., Kozlowski, L. T., Frecker, R. C., & Fagerstrom, K. O. (1991). The fagerstrom test for nicotine dependence: A revision of the Fagerstrom tolerance questionnaire. Br J Addict, 86 (9), 11191127.
Hughes, J. R. (2007). Effects of abstinence from tobacco: Valid symptoms and time course. Nicotine Tob Res, 9 (3), 315327.
Hughes, J. R., Keely, J. P., Niaura, R. S., Ossip-Klein, D. J., Richmond, R. L., & Swan, G. E. (2003). Measures of abstinence in clinical trials: Issues and recommendations. Nicotine Tob Res, 5 (1), 1325.
Hughes, J. R., Keely, J., & Naud, S. (2004). Shape of the relapse curve and long-term abstinence among untreated smokers. Addiction, 99 (1), 2938.
Hughes, J. R., Stead, L. F., & Lancaster, T. (2007). Antidepressants for smoking cessation. Cochrane Database Syst Rev, 1 (1), CD000031.
Hughes, J., Hatsukami, D., Pickens, R., Krahn, D., Malin, S., & Luknic, A. (1984). Effect of nicotine on the tobacco withdrawal syndrome. Psychopharmacology (Berl), 83 (1), 8287.
Hurt, R. D., Dale, L. C., Fredrickson, P. A., Caldwell, C. C., Lee, G. A., Offord, K. P. et al. (1994). Nicotine patch therapy for smoking cessation combined with physician advice and nurse follow-up. One-year outcome and percentage of nicotine replacement. JAMA, 271 (8), 595600.
Jaehne, A., Loessl, B., Barkai, Z., Riemann, D., & Hornyak, M. (2009). Effects of nicotine on sleep during consumption, withdrawal and replacement therapy. Sleep Med Rev, 13 (5), 363377.
Jorenby, D. E., Hatsukami, D. K., Smith, S. S., Fiore, M. C., Allen, S., Jensen, J. et al. (1996). Characterization of tobacco withdrawal symptoms: Transdermal nicotine reduces hunger and weight gain. Psychopharmacology (Berl), 128 (2), 130138.
Jorenby, D. E., Hays, J. T., Rigotti, N. A., Azoulay, S., Watsky, E. J., Williams, K. E. et al. (2006). Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: A randomized controlled trial. JAMA, 296 (1), 5663.
Lerman, C., Kaufmann, V., Rukstalis, M., Patterson, F., Perkins, K., Audrain-McGovern, J. et al. (2004). Individualizing nicotine replacement therapy for the treatment of tobacco dependence: A randomized trial. Ann Intern Med, 140 (6), 426433.
Lerman, C., Roth, D., Kaufmann, V., Audrain, J., Hawk, L., Liu, A. et al. (2002). Mediating mechanisms for the impact of bupropion in smoking cessation treatment. Drug Alcohol Depend, 67 (2), 219223.
Lerman, C., Schnoll, R. A., Hawk, L. W. Jr., Cinciripini, P., George, T. P., Wileyto, E. P. et al. (2015). Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: A randomised, double-blind placebo-controlled trial. Lancet Respir Med, 3 (2), 131138.
Lerman, C., Tyndale, R., Patterson, F., Wileyto, E. P., Shields, P. G., Pinto, A. et al. (2006). Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation. Clinical Pharmacology and Therapeutics, 79 (6), 600608.
Patterson, F., Schnoll, R. A., Wileyto, E. P., Pinto, A., Epstein, L. H., Shields, P. G. et al. (2008). Toward personalized therapy for smoking cessation: A randomized placebo-controlled trial of bupropion. Clinical Pharmacology and Therapeutics, 84 (3), 320325.
Peters, E. N., Fucito, L. M., Novosad, C., Toll, B. A., & O'Malley, S. S. (2011). Effect of night smoking, sleep disturbance, and their co-occurrence on smoking outcomes. Psychol Addict Behav, 25 (2), 312319.
Schnoll, R. A., Patterson, F., Wileyto, E. P., Heitjan, D. F., Shields, A. E., Asch, D. A. et al. (2010). Effectiveness of extended-duration transdermal nicotine therapy: A randomized trial. Ann Intern Med, 152 (3), 144151.
Schnoll, R. A., Patterson, F., Wileyto, E. P., Tyndale, R. F., Benowitz, N., & Lerman, C. (2009). Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: A validation study. Pharmacology, Biochemistry and Behavior, 92 (1), 611.
Sheehan, D. V., Lecrubier, Y., Sheehan, K. H., Janavs, J., Weiller, E., Keskiner, A. et al. (1997). The validity of the Mini International Neuropsychiatric Interview(MINI) according to the SCID-P and its reliability. European Psychiatry, 12 (5), 232241.
Shiffman, S., Patten, C., Gwaltney, C., Paty, J., Gnys, M., Kassel, J. et al. (2006). Natural history of nicotine withdrawal. Addiction, 101 (12), 18221832.
Soldatos, C. R., Kales, J. D., Scharf, M. B., Bixler, E. O., & Kales, A. (1980). Cigarette smoking associated with sleep difficulty. Science, 207 (4430), 551553.
Swan, G. E., Jack, L. M., Javitz, H. S., McAfee, T., & McClure, J. B. (2008). Predictors of 12-month outcome in smokers who received bupropion sustained-release for smoking cessation. CNS Drugs, 22 (3), 239256.
Swan, G. E., & Lessov-Schlaggar, C. N. (2009). Tobacco addiction and pharmacogenetics of nicotine metabolism. Journal of neurogenetics, 23 (3), 262271.
Wetter, D. W., Fiore, M. C., Baker, T. B., & Young, T. B. (1995). Tobacco withdrawal and nicotine replacement influence objective measures of sleep. Journal of Consulting and Clinical Psychology, 63 (4), 658667.

Sleep Disturbance During Smoking Cessation: Withdrawal or Side Effect of Treatment?

  • Rebecca L. Ashare (a1), Caryn Lerman (a2), Rachel F. Tyndale (a3) (a4), Larry W. Hawk (a5), Tony P. George (a3), Paul Cinciripini (a6) and Robert A. Schnoll (a2)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed