Nicotine replacement therapy

Nicotine replacement therapy
A nicotine patch is applied to the left arm
Names
Trade namesNicoderm, Commit, Nicorette, Nicotrol, others[1]
IUPAC name
  • (S)-3-[1-Methylpyrrolidin-2-yl]pyridine
Clinical data
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: D (Evidence of risk)[1]
    Defined daily doseNot established[2]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa601084
    Legal
    License data

    Nicotine replacement therapy (NRT) is a medically-approved way to take nicotine by means other than tobacco.[3] It is used to help with quitting smoking or stopping chewing tobacco.[1][4] It increases the chance of quitting smoking by about 55%.[5] Often it is used along with other behavioral techniques.[1] NRT has also been used to treat ulcerative colitis.[1] Types of NRT include the adhesive patch, chewing gum, lozenges, nose spray, and inhaler.[1] The use of multiple types of NRT at a time may increase effectiveness.[6][7]

    Common side effects depend on the formulation of nicotine.[1] Common side effects with the gum include nausea, hiccups, and irritation of the mouth.[1] Common side effects with the patch include skin irritation and a dry mouth while the inhaler commonly results in a cough, runny nose, or headaches.[1] Serious risks include nicotine poisoning and continued addiction.[1] They do not appear to increase the risk of heart attacks.[5] There are possible harms to the baby if used during pregnancy.[1][8] Nicotine replacement therapy works by reducing cravings caused by nicotine addiction.[1][9]

    They were first approved for use in 1984, in the United States.[1] Nicotine replacement products are on the World Health Organization's List of Essential Medicines.[10][11] They are available as generic medication.[1] In the United States a month of patches or gum is between US$100 and US$200 while the other forms are more expensive.[12]

    Medical uses

    Nicotine pastilles
    An oral nicotine spray

    Nicotine replacement therapy, in the form of gum, patches, nasal spray, inhaler and lozenges all improve the ability of people trying to quit tobacco products.[5] Nicotine replacement therapy is as effective as medications, such as bupropion, in helping people quit smoking for at least 6 months.[13] All forms of nicotine replacement therapy, including nicotine gum, patches, nasal spray, inhalers, and lozenges, have similar success rates in terms of helping people stop smoking. However, the likelihood that someone will stick to a certain treatment varies, with compliance being the highest with nicotine patches, followed by nicotine gum, inhalers, and nasal sprays.[14] Using a few different nicotine replacement methods in combination may improve success rates in stopping tobacco use.[13][15] Additionally, using nicotine replacement with counseling has been proven to improve tobacco abstinence rates.[16][17] These other strategies include: creating a plan to quit and utilizing quit programs, a quit phone line, or app that provides tips and inspiration to help quit.[15]

    Using nicotine replacement therapy to quit smoking should be considered for people who are severely dependent on nicotine.[18] People who are severely dependent include those who smoke: more than 1 pack per day, within 5 minutes of awakening, while ill, when they wake up in the middle of the night, to ease withdrawal signs and symptoms.[18]

    Nicotine replacement products are most beneficial for heavy smokers who smoke more than 15 cigarettes per day. There are not enough studies to show whether NRT helps those who smoke fewer than 10 cigarettes per day.[17]

    Effectiveness

    Evaluation of NRT in real-world studies produces more modest outcomes than efficacy studies conducted by the industry-funded trials. The National Health Service (NHS) in England has a smoking cessation service based on pharmacotherapy in combination with counseling support. An Action on Smoking and Health (UK) (ASH) report claims that the average cost per life year gained for every smoker successfully treated by these services is less than £1,000 (below the NICE guidelines of £20,000 per QALY (quality-adjusted life year). However, the investment in NHS stop smoking services is relatively low. A comparison with treatment costs for illicit drug users shows that £585 million is committed for 350,000 problem drug users compared to £56 million for 9 million users of tobacco. This is £6.20 for each smoker, compared to £1,670 per illegal drug user.[19]

    The claims for high efficacy and cost-effectiveness of NRT have not been substantiated in real-world effectiveness studies.[20][21][22] Pierce and Gilpin (2002) stated their conclusion as follows: “Since becoming available over the counter, NRT appears no longer effective in increasing long-term successful cessation” (p. 1260).[22] Efficacy studies, which are conducted using randomized controlled trials, do not transfer very well to real-world effectiveness. Bauld, Bell, McCullough, Richardson and Greaves (2009) reviewed 20 studies on the effectiveness of intensive NHS treatments for smoking cessation published between 1990 and 2007.[23] Quit rates showed a dramatic decrease between 4-weeks and one year. A quit rate of 53% at four weeks fell to only 15% at 1 year. Younger smokers, females, pregnant smokers and more deprived smokers had lower quit rates than other groups.

    The efficacy for each of the formulations alone (lozenges, nasal spray, gum, and transdermal patch) to aid in smoking cessation is equal.[24] Efficacy increases 15% to 36% with combining treatments such as gum and lozenges. Higher doses increase the chance of stopping smoking for a period of six months and more. For patches, the most efficient doses were 25 mg worn over 16 hours or 21 mg worn over 24 hours. The evidence suggests that 4 mg nicotine gum leads to higher quit rates compared with 2 mg in heavy smokers.[25]

    Pregnancy

    Nicotine is not safe to use in any amount during pregnancy.[26] Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke.[27] There are possible harms to the baby if NRT is used during pregnancy.[1][8] Thus, pregnant women and those who are breastfeeding should also consult a physician before initiating NRT.[28] The gum, lozenge, and nasal spray are pregnancy category C. The transdermal patch is pregnancy category D. The transdermal patch is considered less safe for the fetus because it delivers continuous nicotine exposure, as opposed to the gum or lozenge, which delivers intermittent and thus lower nicotine exposure.[29][30]

    Strong evidence suggests that nicotine cannot be regarded as a safe substance of cigarette use.[29] Nicotine itself could be at least partly responsible for many of the adverse after birth health results related to cigarette use while the mother was pregnant.[29] There is evidence that nicotine negatively affects fetal brain development and pregnancy outcomes.[31] There is also risk of stillbirth and pre-term birth.[32] Nicotine use will probably harm fetal neurological development.[33] Risks to the child later in life from nicotine exposure during pregnancy include type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.[34] Nicotine exposure during pregnancy can result in attention deficit hyperactivity disorder (ADHD) and learning disabilities in the child. It also puts the child at increased risk for nicotine addiction in the future.[29]

    Pregnant women should consider behavioral therapy before NRT is considered.[1]

    Youth

    In people under the age of 18, a physician is often consulted before starting NRT.[28] The evidence suggests that exposure to nicotine between the ages of 10 and 25 years causes lasting harm to the brain and cognitive ability.[35] Evidence is unclear whether adolescents gain benefit from cognitive-behavioral therapy or smoking cessation over the long-term as of 2017.[36] Most tobacco users are under-eighteens when they start, and almost no-one over the age of 25 starts using.[37]

    Cardiovascular conditions

    While there is no evidence that NRT can increase the risk of heart attacks,[5] individuals with pre-existing cardiovascular conditions or recent heart attacks should consult a physician before initiating NRT.[28]

    Smoking is known to cause cardiovascular disease such as coronary heart disease, hypertension, heart attack, stroke, and peripheral artery disease. Cigarette smoking is the cause of 20% of all cardiovascular deaths in the United States, which is the leading cause of mortality.[38]

    Other conditions

    Nicotine replacement therapies should be used cautiously in individuals with the following conditions: severe reactive airway diseases (for nasal spray), chronic nasal disorders such as sinusitis, polyps, rhinitis, or allergy (for nasal spray), diabetes (insulin-dependent), gastrointestinal diseases such as esophagitis, active gastric or peptic ulcer disease, liver problems, hyperthyroidism, pheochromocytoma, phenylketonuria (for lozenges), renal problems, and skin conditions such as psoriasis or dermatitis (for transdermal patch).[39]

    Dosage

    The defined daily dose is not established[2]

    Side effects

    Possible side effects of nicotine.[40]

    Some side effects are caused by the nicotine, and are common to NRT products.[41][34] Other common side effects depend on the formulation of nicotine.[1] Common side effects with the gum include nausea, hiccups, and irritation of the mouth.[1] Common side effects with the patch include skin irritation and a dry mouth while the inhaler commonly results in a cough, runny nose, or headaches.[1] To minimize local skin reactions from the patch, the application site should be moved daily.[42] The nicotine patch can also cause strange dreams if worn while asleep.[17] Nasal sprays commonly cause nasal irritation, watering eyes, and coughing.[41]

    Serious risks include nicotine poisoning, which includes symptoms like visual disturbances, hyper-salivation, nausea, and vomiting; and continued addiction to nicotine products.[1] Avoiding smoking and other products with nicotine is recommended since it may lead to nicotine overdose.[43] Although overdose is rare, it can be problematic, especially in children and pets.[44] The symptoms of nicotine overdose include headache, pale skin and mouth, belly pain, weakness, diarrhea, tremors or seizures, agitation, confusion, restlessness, high or low blood pressure, fast or irregular heartbeat, fast breathing, and cold sweats.[18]

    Limited evidence exists regarding long-term NRT use, and concerns exist that long-term NRT use could raise cancer risk, due in part to the generation of carcinogens.[45]

    Mechanism of action

    Nicotine replacement therapy works by reducing cravings due to nicotine addiction.[1][9] Smoking cigarettes releases high doses of nicotine to the brain in a matter of seconds as opposed to low doses released over a period of minutes to hours by the various forms of nicotine replacement therapy.[42] Nicotine from NRT does not reach as high a concentration in the blood as does nicotine from smoke inhalation due to different absorption methods. NRT relies on systemic venous absorption, whereas nicotine from cigarettes reaches the arterial system.[42] Nicotine replacement products vary in the time it takes for the nicotine to enter the body and the total time nicotine stays in the body.[16] The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk.[46] It is possible to become dependent on some NRTs.[47]

    Nicotine patches are applied to the skin and continuously administer a stable dose of nicotine slowly over 16–24 hours.[16][30] Nicotine gum, nicotine sprays, nicotine toothpicks, nicotine sublingual tablets, and nicotine lozenges administer nicotine orally with quicker nicotine uptake into the body but lasting a shorter amount of time.[48] Nicotine inhalers are metered-dose inhalers that administer nicotine through the lungs and mucous membranes of the throat quickly, lasting for a short amount of time. For example, blood nicotine levels are the highest 5–10 minutes after using the nicotine nasal spray, 20 minutes after using a nicotine inhaler or chewing nicotine gum, and 2–4 hours after using a nicotine patch.[16][49]

    Society and culture

    NRT products were first approved for use in the United States in 1984.[1] Nicotine replacement products are on the World Health Organization's List of Essential Medicines.[10] They are available as generic medication.[1] In the United States a month of patches or gum is between US$100 and US$200 while the other forms are more expensive.[12]

    Cost

    In the United States a month of patches or gum is between US$100 and US$200 while the other forms are more expensive.[12]

    • Nicotine costs (US)
      Nicotine costs (US)
    • Nicotine prescriptions (US)
      Nicotine prescriptions (US)

    Formulations

    Availability in the United States [15]
    NRT Types Availability How it works[50]
    Patch Over-the-Counter Steadily administers a low dose of nicotine through a patch placed on the skin
    Lozenge Over-the-Counter Slowly dissolves to releases nicotine through a hard candy
    Gum Over-the-Counter Chewing the gum releases nicotine
    Inhaler Prescription Inhaling through the mouthpiece administers nicotine
    Nasal Spray Prescription Spraying a pump bottle into nose administers nicotine

    In 2015, the United States Public Health Service listed seven agents for the stopping of tobacco, which included 5 nicotine replacement treatments (nicotine patches, gum, lozenges, inhalers, and nasal sprays) and 2 oral medications (bupropion and varenicline). Other NRT options are available, including nicotine mouth sprays and sublingual tablets.[51]

    The nicotine patch is a once-daily, longer-acting form of NRT. An advantage of the nicotine patch is its simple compliance; it does not require active use throughout the day.[42] The gum, lozenge, sublingual tablet, oral inhaler, and nasal spray are acutely dosed products, providing the user with the benefit and ability of self-titrating based on cravings.[42]

    Trade names include Nicotex, Nicorette, Nicoderm, Nicogum, Nicotinell, Thrive and Commit Lozenge.

    Dosing

    The dose of nicotine replacement therapy products is generally based on if the user is considered a heavy, average, or light smoker.[18]

    General guideline[18]
    Type of User Dose of NRT Amount of cigarettes Amount of smokeless tobacco
    Light Lower <10 cigarettes daily <2 snuff cans or tobacco pouches weekly
    Average Moderate 10-20 cigarettes daily 2-3 snuff cans or tobacco pouches weekly
    Heavy Higher 1 or more pack of cigarettes daily >3 snuff cans or tobacco pouches weekly

    A cigarette delivers an average of 1 mg to 3 mg of the nicotine contained in it. NRT products typically aim to parallel this, but the amount of nicotine absorbed by the user is less than the original dose.

    Nicotine nasal sprays are formulated in doses of lowest strength, available in 0.5 mg and 1 mg strengths.

    Nicotine lozenges deliver doses as low as 1 mg up to 4 mg. It is not chewed as the gum would be, and dissolves in approximately 30 minutes.[42] This formulation may be preferred by those individuals who do not find gum chewing to be acceptable.

    Nicotine gum is available in doses of 2 mg and 4 mg. Using 4 mg nicotine gum versus 2 mg gum increases the likelihood of successful smoking cessation.[25] When using the gum, acidic beverages like soda, coffee, or beer should be avoided 15 minutes prior and during use because they can impede proper absorption of nicotine.[42]

    Nicotine inhalers come in 10 mg and 15 mg cartridge strengths and typically deliver around 4 mg in one dose.[52] The inhaler may be preferred in individuals who want to satisfy the hand-to-mouth ritual that smoking provides.[42]

    Transdermal patches deliver between 5 mg and 52.5 mg of nicotine, which results in plasma levels similar to that of heavy smokers. Combining nicotine patch treatment with a faster nicotine-delivery means, like nicotine gum or spray, improves the likelihood of successful treatment.[25][5]

    Economics

    In the United States, a month of patches or gum is between US$100 and US$200 as of 2015 while the other forms are more expensive;[12] in the UK lozenges are the cheapest. In the United States, a month of patches is about US$170.[1]

    Average wholesale cost[53]
    Formulation Brand name Generic Strength Package size Average wholesale price (USD)
    Patch Nicoderm CQ Yes 7 mg/24 hours 14 patches $23.99
    14 mg/24 hours
    21 mg/24 hours
    Lozenge Nicorette Yes 2 mg 20 lozenges $10.92
    4 mg
    Gum Nicorette Yes 2 20 lozenges $8.99
    4
    Intranasal Nicotrol NS No 10 mg/1 mL 10 mL $524.87
    Inhaler Nicotrol inhaler No 4 mg/ 1 actuation 168 actuations $499.87

    Not approved as NRTs

    Snus and nasal snuff also allow for nicotine administration outside of tobacco smoking.[54]

    Nicotine infused toothpicks are another product that has been available in the United States since at least 2013. They can have a total nicotine delivery that is comparable to that of nicotine gum.[48] Nicotine toothpicks generally are infused with food-grade flavorings and 3 mg of nicotine which is similar to that of other oral products and what some cigarettes deliver.[55][56] In spite of these similarities, as of 2018 they have been a subject of controversy. News outlets have expressed the concern that these products have high appeal to minors wanting to experiment with nicotine due to the multitude of sweet flavors, ease of use, speed of use, and discrete nature.[57][58][59]

    In 2015, NRT sales fell for the first time since 2008 while sales for e-cigarettes continued to increase at a substantial rate. This had led to speculation that UK smokers are trying to quit with e-cigarettes rather than NRT methods.[60]

    E-cigarettes are often, although not always, designed to look and feel like cigarettes. They have been marketed as less harmful alternatives to cigarettes,[61] but very few are as yet approved as NRTs in any jurisdiction. Some electronic cigarettes have coarsely adjustable nicotine levels. Some healthcare groups have hesitated to recommend e-cigarettes for quitting smoking, because of limited evidence of effectiveness and safety.[62]

    The U.S. Food and Drug Administration (FDA) has a list of additional tobacco products Archived 2019-08-08 at the Wayback Machine they are seeking to regulate, including electronic cigarettes.[63] Most approved NRT products have been approved for over 20 years,[64] however the FDA has also approved nicotine inhalers as a form of NRT.[65][66]

    Future approaches of NRT could include nicotine preloading, true pulmonary inhaler, and nicotine vaccines.[5] Nicotine preloading, otherwise known as pre-cessation or pre-quitting NRT, has found that using the patch for a few weeks prior to the quit date produces significantly higher quit rates than if it was started on the quit day.[5] The true pulmonary inhaler would deliver nicotine to the lungs in a manner that more resembles cigarette smoking, which would provide better relief of background cravings as well as acute cravings.[5] Nicotine vaccines are under investigation as a method to treat tobacco dependence by means of priming the body to mount an immune response against nicotine.[5]

    Other formulations

    Nicotine polacrilex[67] is nicotine bound to an ion-exchange resin (polymethacrylic acid). It is added to gums and hard lozenges used for nicotine replacement therapy in smoking cessation.[68][69] The use of the polymer as a delivery system maximizes the amount of nicotine released and absorbed by the oral mucosa. 80 to 90 percent of the nicotine released from the gum is absorbed by the mouth. Side effects of the gum include bad taste, nausea, dyspepsia, and stomatitis.

    The cost in the U.S. is $16 (USD) for 20 gum(s) transmucosal gum 2 mg [70]

    • Nicotine Polacrilex costs (US)
      Nicotine Polacrilex costs (US)
    • Nicotine Polacrilex prescriptions (US)
      Nicotine Polacrilex prescriptions (US)

    See also

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 "Nicotine". The American Society of Health-System Pharmacists. Archived from the original on 18 December 2015.
    2. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 1 July 2021. Retrieved 22 September 2020.
    3. ↑ Jain R, Majumder P, Gupta T (2013). "Pharmacological intervention of nicotine dependence". BioMed Research International. 2013: 278392. doi:10.1155/2013/278392. PMC 3891736. PMID 24490153.
    4. ↑ Smith KD, Scott MA, Ketterman E, Smith PO (April 2005). "Clinical inquiries. What interventions can help patients stop using chewing tobacco?". The Journal of Family Practice. 54 (4): 368–9. PMID 15833231.
    5. 1 2 3 4 5 6 7 8 9 Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T (May 2018). Cochrane Tobacco Addiction Group (ed.). "Nicotine replacement therapy versus control for smoking cessation". The Cochrane Database of Systematic Reviews. 5: CD000146. doi:10.1002/14651858.CD000146.pub5. PMC 6353172. PMID 29852054.
    6. ↑ McDonough M (August 2015). "Update on medicines for smoking cessation". Australian Prescriber. 38 (4): 106–11. doi:10.18773/austprescr.2015.038. PMC 4653977. PMID 26648633. Evidence suggests that combinations of nicotine replacement therapy may be more effective than using a single formulation
    7. ↑ Cahill K, Stevens S, Perera R, Lancaster T (May 2013). "Pharmacological interventions for smoking cessation: an overview and network meta-analysis". The Cochrane Database of Systematic Reviews. 5 (5): CD009329. doi:10.1002/14651858.CD009329.pub2. PMID 23728690. Archived from the original on 2021-08-28. Retrieved 2019-11-21. Combination NRT also outperformed single formulations
    8. 1 2 De Long NE, Barra NG, Hardy DB, Holloway AC (December 2014). "Is it safe to use smoking cessation therapeutics during pregnancy?". Expert Opinion on Drug Safety. 13 (12): 1721–31. doi:10.1517/14740338.2014.973846. PMID 25330815.
    9. 1 2 "Nicotine Replacement Therapy for Smoking Cessation or Reduction: A Review of the Clinical Evidence". Canadian Agency for Drugs and Technologies in Health. 16 January 2014. PMID 24741730. {{cite journal}}: Cite journal requires |journal= (help)
    10. 1 2 World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
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    12. 1 2 3 4 Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 441. ISBN 9781284057560.
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    14. ↑ Hajek P, West R, Foulds J, Nilsson F, Burrows S, Meadow A (September 1999). "Randomized comparative trial of nicotine polacrilex, a transdermal patch, nasal spray, and an inhaler". Archives of Internal Medicine. 159 (17): 2033–8. doi:10.1001/archinte.159.17.2033. PMID 10510989.
    15. 1 2 3 "Using Nicotine Replacement Therapy | Smokefree". smokefree.gov. Archived from the original on 2019-10-23. Retrieved 2019-10-23.
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    19. ↑ "Action on Smoking & Health, 2008" (PDF). Archived from the original (PDF) on 24 September 2015. Retrieved 27 August 2015.
    20. ↑ Doran et al. (2006), pp. 758–766
    21. ↑ Ferguson, et al. (2006). Addiction: 59–69. {{cite journal}}: Missing or empty |title= (help)
    22. 1 2 Pierce JP, Gilpin EA (September 2002). "Impact of over-the-counter sales on effectiveness of pharmaceutical aids for smoking cessation". JAMA. 288 (10): 1260–4. doi:10.1001/jama.288.10.1260. PMID 12215133.
    23. ↑ Bauld L, Bell K, McCullough L, Richardson L, Greaves L (March 2010). "The effectiveness of NHS smoking cessation services: a systematic review". Journal of Public Health. 32 (1): 71–82. doi:10.1093/pubmed/fdp074. PMID 19638397.
    24. ↑ Abuse, National Institute on Drug. "What are treatments for tobacco dependence?". www.drugabuse.gov. Archived from the original on 2019-11-19. Retrieved 2019-11-20.
    25. 1 2 3 Lindson N, Chepkin SC, Ye W, Fanshawe TR, Bullen C, Hartmann-Boyce J (April 2019). "Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation". The Cochrane Database of Systematic Reviews. 4: CD013308. doi:10.1002/14651858.CD013308. PMC 6470854. PMID 30997928.
    26. ↑ Alawsi F, Nour R, Prabhu S (August 2015). "Are e-cigarettes a gateway to smoking or a pathway to quitting?". British Dental Journal. 219 (3): 111–5. doi:10.1038/sj.bdj.2015.591. PMID 26271862.
    27. ↑ "State Health Officer's Report on E-Cigarettes: A Community Health Threat" (PDF). California Department of Public Health. January 2015. Archived (PDF) from the original on 2019-01-09. Retrieved 2018-12-25.
    28. 1 2 3 "FDA 101: Smoking Cessation Products". U.S. Food and Drug Administration. Archived from the original on 3 November 2014. Retrieved 28 October 2014.
    29. 1 2 3 4 Bruin JE, Gerstein HC, Holloway AC (August 2010). "Long-term consequences of fetal and neonatal nicotine exposure: a critical review". Toxicological Sciences. 116 (2): 364–74. doi:10.1093/toxsci/kfq103. PMC 2905398. PMID 20363831.
    30. 1 2 Oncken C, Dornelas E, Greene J, Sankey H, Glasmann A, Feinn R, Kranzler HR (October 2008). "Nicotine gum for pregnant smokers: a randomized controlled trial". Obstetrics and Gynecology. 112 (4): 859–67. doi:10.1097/AOG.0b013e318187e1ec. PMC 2630492. PMID 18827129.
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    32. ↑ "The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General, Chapter 9 – Reproductive Outcomes" (PDF). Surgeon General of the United States. 2014: 107–138. PMID 24455788. Archived from the original (PDF) on 2019-03-15. Retrieved 2018-11-19. {{cite journal}}: Cite journal requires |journal= (help)
    33. ↑ England LJ, Kim SY, Tomar SL, Ray CS, Gupta PC, Eissenberg T, et al. (31 December 2010). "Non-cigarette tobacco use among women and adverse pregnancy outcomes". Acta Obstetricia et Gynecologica Scandinavica. 89 (4): 454–64. doi:10.3109/00016341003605719. PMC 5881107. PMID 20225987. The use of any products containing nicotine likely will have adverse effects of fetal neurological development.
    34. 1 2 Schraufnagel DE, Blasi F, Drummond MB, Lam DC, Latif E, Rosen MJ, et al. (September 2014). "Electronic cigarettes. A position statement of the forum of international respiratory societies". American Journal of Respiratory and Critical Care Medicine. 190 (6): 611–8. doi:10.1164/rccm.201407-1198PP. PMID 25006874. Archived from the original on 2021-08-28. Retrieved 2019-11-21.
    35. ↑ U.S. Department of Health and Human Services, Public Health Service Office of the Surgeon General Rockville, MD (2016). "E-Cigarette Use Among Youth and Young Adults: A Report of the Surgeon General". Archived from the original on 1 January 2019. Retrieved 15 November 2018. Evidence for this report was gathered from scientific research that included one or more of three age groups. These age groups included young adolescents (11–13 years of age), adolescents (14–17 years of age), and young adults (18–24 years of age). Some studies refer to the younger groups more generally as youth... Of concern with regard to current trends in e-cigarette use among youth and young adults, the evidence suggests that exposure to nicotine during this period of life may have lasting deleterious consequences for brain development, including detrimental effects on cognition {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
    36. ↑ Fanshawe TR, Halliwell W, Lindson N, Aveyard P, Livingstone-Banks J, Hartmann-Boyce J (November 2017). "Tobacco cessation interventions for young people". The Cochrane Database of Systematic Reviews. 11: CD003289. doi:10.1002/14651858.cd003289.pub6. PMC 6486118. PMID 29148565.
    37. ↑ U.S. Department of Health and Human Services, Public Health Service Office of the Surgeon General Rockville, MD (2016). "E-Cigarette Use Among Youth and Young Adults: A Report of the Surgeon General". Archived from the original on 1 January 2019. Retrieved 15 November 2018. The majority of tobacco users start before they are 18 years of age, and almost no one starts after age 25 {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
    38. ↑ "How Smoking Affects Heart Health". FDA. FDA. 2019-04-18. Archived from the original on 2019-12-12. Retrieved 6 November 2019.
    39. ↑ "Nicotine Monograph for Professionals". Drugs.com. Archived from the original on 18 December 2015. Retrieved 20 November 2019.
    40. ↑ Detailed reference list is located on a separate image page
    41. 1 2 "Nicotine Side Effects". Drugs.com. Drugs.com. 21 January 2019. Archived from the original on 13 August 2021. Retrieved 19 November 2018.
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    43. ↑ "Nicotine Replacement Therapy for Quitting Tobacco". www.cancer.org. Archived from the original on 23 October 2019. Retrieved 20 November 2019.
    44. ↑ "Nicotine Replacement Therapy for Quitting Tobacco". Archived from the original on 2019-10-23. Retrieved 2019-10-28.
    45. ↑ Wilder, Natalie; Daley, Claire; Sugarman, Jane; Partridge, James (April 2016). "Nicotine without smoke: Tobacco harm reduction". UK: Royal College of Physicians. p. 58. Archived from the original on 2016-05-05.
    46. ↑ Parrott AC (July 2015). "Why all stimulant drugs are damaging to recreational users: an empirical overview and psychobiological explanation" (PDF). Human Psychopharmacology. 30 (4): 213–24. doi:10.1002/hup.2468. PMID 26216554. Archived (PDF) from the original on 2018-11-19. Retrieved 2018-11-19.
    47. ↑ Hughes JR (1989). "Dependence potential and abuse liability of nicotine replacement therapies". Biomedicine & Pharmacotherapy. 43 (1): 11–7. doi:10.1016/0753-3322(89)90185-6. PMID 2659095.
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