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I I I I I I I RISK-BENEFIT ASSESSMENT Drug Safety 8 rle 49-56. 1993 0 114-5916,93,0001 -0049 Sp-300 0 ~ adis International Limited All riehts resencd QaS+ 123 Risk-Benefit Assessment of Nicotine Preparations in Smoking Cessation John R. Hughes Departments of Psychiatry. Psychology and Famiiy Practice. University of Vermont. Burlington. Vermont. USA Contents 49 SO Summary I. Possible Adverse Efiects of Nicotine ~ 52 2. 'vicoune Intoxication 52 3. Determinants of the Safety and Toxicity of Nicotine 52 4. Safety and Toxicity of Nicotine Replacement Products 52 4.1 Nicotine Polacnlex ! 53 4.2 Transdermal Nicotine , 53 4.3 Nicotine Nasal Spray 53 4.4 Nicotine Aerosols and Vapours 54 4.5 Other Nicotine Preparations ~ 54 5. Benefits of Nicotine Therapy 54 6. Risk-Benefit of Nicotine Therapy 54 6.1 Risk-Benefit in Special Populations 54 6.1.1 Pregnancy ~ 54 6.1.2 Cardiovascular Diseases 55 6.1.3 Children and the Elderly 55 6.1.4 Temporary Use During Hospitalisation 55 7. Future Research Needs I I I I I I I I I SuAtHtaly Nicotine influences many risk factors for cardiovascular disease, peptic ulcer disease, preg- nancy complications and wound healing: however, whether nicotine itself actually causes or ag- gravates these diseases has not been well demonstrated. The safety of nicotine preparations for smoking cessation depends on the population, formulation, route of administration, dose, and frequency and duration of use. Major adverse effects of nicotine polacrilex and tnnsderrnal ni- cotine are very rare. Nicotine therapy usually doubles long term abstinence rates and is especially beneficial to highly dependent smokers. Nicotine replacements produce lower nicotine concen- trations than cigarettes, and no tar and carbon monoxide: thus, it is difficult to justify absolute contraindications to these products. Decisions on the use of nicotine preparations in pregnancy, coronary disease, etc., must consider not only the medical status of patients but also their like- lihood of stopping smoking with and without the help of nicotine replacement.

1 '() Drtaq St1iPrtY ~li i v4? I I I I I I I I I I I I I I I Several nicotine replacement products have either been marketed. e.g. nicotine polacrilex (ni- cotine gum) [Fagerstrom i988] and transdermai nicotine (nicotine patch) [Fagerstrom et al. 1992: Palmer & Faulds 199?]. or are under development. e.g. nasal nicotine spray (Jarvis et al. 1987) and nicotine inhalers (Hajek et al. 1989). The safety and toxicity of these products have been reviewed pre- viouslv (Benowitz 1988a. 1989, 1991a.b: Christen. McDonald 1988: Hughes 1986a. 1988: US De- partment of Health and Human Services 1988a). The present article briefly updates these previous reviews. suggests guidelines for use of nicotine re- placement in at-risk populations and suggests fu- ture avenues of research. Since the article focuses on clinical applications, intravenous and subcutan- eous nicotine are not discussed. 1. Possible Adverse Effects of Nicotine Most of the harmful effects of tobacco arise from the tar and carbon monoxide delivered by smoking (US Department of Health and Human Services 1990). The role of nicotine itself in either causing or aggravating diseases is often unclear because we have no epidemiological data of the effects of ni- cotine that are independent of the effects of tar, carbon monoxide or the other chemicals in cigar- ettes. For example. nicotine appears to adversely in- fluence several cardiovascular parameters (Benow- itz 1991a: US Department of Health and Human Services 1988a) [fig. 1]. Nicotine increases heart rate, blood pressure, cardiac output, stroke volume and vasoconstriction. It also may increase very low density and low density lipoproteins and decrease high density lipoprotein. In nonhumans, nicotine also increases platelet activation and aggregation, injures endothetial cells and increases thrombus formation. In patients with coronary heart disease (CHD), nicotine may cause coronary vasoconstric- tion, arrhythmogenesis and increased cardiac de- mand. Despite this harmful profile, it has been dif- ficult to demonstrate that nicotine itself contributes to the association of cigarette smoking and CHD. For example. many pipe and cigar smokers ingest significant amounts of nicotine yet most studies have not found increases in CHD in this group. In addition, if nicotine is important to CHD. then switching to low nicotine cigarettes should de- crease CHD: however, the evidence for this is not clear (US Department of Health and Human Serv- ices 1990). This may be due to the fact that when smokers switch to low nicotine cigarettes they smoke more frequently and more intensely; thus, nicotine exposure does not decrease as much as projected (DeGrandpre et al. 1992). In terms of carcinogenesis, nicotine can be ni- trosated to form nitrosamine, a known carcinogen (Hoffman 1989). However, in ncnhuman studies, nicotine has repeatedly failed to show carcinogenic effects (Levy & Martin 1989). One study suggested nicotine may act as a co-carcinogen but this effect was not replicated in a later study. The role of nicotine in the adverse effects of smoking in pregnancy is still debatable (Benowitz 1991 b: US Department of Health and Human Services 1980). The low birth weight of children of smokers has been attributed to nicotine-induced vasoconstriction of the placenta. In addition, in the second trimester nicotine increases fetal heart rate and in the third trimester decreases fetal heart and respiratory rates. On the other hand, low birth weight has also been ascribed to hypoxic effects from carbon monoxide, which binds to haemoglo- bin much more readily than oxygen. Nicotine may affect several other medical dis- orders. Nicotine could promote ulcer disease by: (a) increased acid output; (b) decreased pancreatic bicarbonate; (c) decreased mucosal barrier, and (d) poor oesophageal and pyloric sphincter function causing reflux. Thus, much of the effect of smoking on aggravating ulcer formation and preventing treatment response has been attributed to nicotine (US Department of Health and Human Services I988a). The vasoconstrictive effect of nicotine has been cited as a cause of poor wound healing (US Department of Health and Human Services 1988a). Also, high doses of nicotine in nonhumans can in- I I I

I I I I I I I I I I 1 I I I I I I I Risk-Benefit .4ssessment of Nicotine Preperations Hyperlip,oaemia Endotheliaf injury Platelet activation thrombosis T Sympathoatlrenal actlvatbn Haemodynamic stress Meohanlsms - --1110. PossiWe -~ Probable D@flnrte Increased dreulating catechoaarrnnes Premature atherosclerosis Vascular stenosis or ocdusion ~ iscfsaernia or irtFaresion ~ Arthythmias Suddan death Carbon monoxide Decreased oxygen transport Fig. 1. Schematic summary of possible mechanisms by which nicotine contnbutes to coronary heart disease. T,A, = throm- boxane A, (from Benowttz 1991a1 with permission). crease respiratory elastase and bronchoconstriction (US Department of Health and Human Services 1984). The most prominent adverse behavioural effect of nicotine is dependence (US Department of Health and Human Services 1988b). Although def- initions of dependence vary, there is a growing consensus that inability to stop, use of drug despite harm, withdrawal, etc., are indicators of depend- ence (American Psychiatric Association 1987). Re- cent surveys suggest about half of smokers fulfil standardised criteria for dependence based on the above features (Breslau et al. 1991: Hale et al. 1992). Several lines of evidence indicate this dependence is due to the nicotine in cigarettes (US Department of Health and Human Services 1988b). These in- clude: (a) nicotine replacement (via gum or patch) decreases withdrawal symptoms: (b) withdrawal occurs upon cessation of all nicotine-containing products (e.g. snuff, chewing tobacco. etc.): (c) withdrawal occurs upon abrupt cessation of nico- tine alone: (d) some withdrawal occurs switching Coronary vasoconstnetion I Increased heart rate, myoCardiai conttactrlity to low nicotine cigarettes: (e) nicotine replacement increases rates of abstinence from smoking: and (f) some smokers persist in long term use of nicotine alone (via nicotine gum) despite recommendations to stop. On the other hand, in contrast to other drugs of dependence, nicotine intoxication does not pro- duce behaviour typically associated with drug in- toxication, such as impaired judgement and con- fusion. In addition. chronic nicotine use does not appear to produce altered mood. psychotic fea- tures, dementia. etc., that are sometimes the se- qualae of other types of drug dependence. Another possible adverse event of recent inter- est is the association of smoking with several psy- chiatric disorders (Breslau et al. 1991: Glassman et al. 1990). Although smoking precedes the onset of psychiatric disorders and there are some theoreti- cal reasons to suspect nicotine as a causal agent, whether the association of smoking and psychiatric disorders is causal and due to the nicotine in cig- arettes is unclear (Hughes 1988b). I

I j? rJruz .Sate'tt' Y 'li Ivvj I I I I I I I I I I I I I I I I I 2. Nicotine Intoxication Large doses of nicotine cause abdominal pain, dizziness, headache. nausea, pallor, palpitation, sweating, vomiting and weakness (Benowitz 1986: US Department of Health and Human Services 1988a). Most cases arise from insecticide poisoning either orally or via absorption through the skin (green tobacco sickness). Mild cases can also occur with nicotine replacement therapy. 3. Determinants of the Safety and Toxicity of Nicotine Several factors play a clinically significant role in determining the safety of nicotine (Benowitz 1988a.b: US Department of Health and Human Services 1988a). First, different routes of admin- istration produce different rates and amounts of absorption of nicotine. Inhalation of nicotine produces a rapid bolus of high concentrations of nicotine. These boli enter the arterial circulation and then the brain without first being distributed throughout the systemic cir- culation. Peak concentrations are reached in ap- proximately 15 to 30 sec. Many investigators be- lieve this rapid bolus effect is essential to the reinforcing effects of nicotine. Besides cigarettes, nicotine aerosols, vapors and inhalers use the in- haled route. Nasal nicotine spray produces an ab- sorption pattern that is rapid but not as rapid as that of inhaled nicotine. When given orally, much of the nicotine ab- sorbed from the gastrointestinal tract is inactivated by first-pass metabolism (Benowitz 1988b). Buccal absorption via polacrilex or buccal tablets pro- duces gradual absorption that peaks over 15 to 30 min (Benowitz 1988a,b). This absorption is sub- stantially dec teased with acidification; thus, buffers added to gum increase and acidic substances (e.g. carbonated beverages) decrease buccal absorption of nicotine. Nicotine readily passes through the skin. Trans- dettnal nicotine produces a slow onset of nicotine which peaks 4 to 8 hours after first application and then remains steady while the patch is worn (Fa- gerstrom et al. 1992: Palmer & Faulds 1992). Dosage is a factor in assessing the effects of any drug. This is especially true with nicotine as its ef- fects vary widely across doses (Henningfield & Woodson 1989). For example, some nicotinic ef- fects are bidirectional, with high and low doses producing opposite effects. Also, some effects are highly related to dose and with some effects, low doses may produce effects equivalent to those of higher doses. A third major factor is acute and chronic tol- erance (US Department of Health and Human Services 1988b). Acute tolerance to nicotinic ef- fects in a cigarette occurs with each cigarette and across a day such that the effect of the first admin- istration of the waking day is more potent than later administrations. Chronic tolerance occurs to aversive effects such as nausea and vomiting, such that the effects of nicotine differ in never, current and ex-smokers. Another, less well explored factor is population. Surprisingly, direct comparisons of the acute ef- fects of nicotine across age, sex and racial groups have rarely been studied. Also, although there are some data on the effects of nicotine across medical groups (e.g. those with vs those without CHD), whether those with a history of non-nicotine drug abuse, psychiatric problems or other medical prob- lems (e.g. Alzheimer's patients) differ in their sub- jective reactions or tolerance to nicotine has only rarely been studied (Newhouse & Hughes 1991). Population differences are plausible given that re- sponses to nicotine are substantially influenced by genetic factors and the fact that people self-select into smoking categories (Hughes 1986b). A final important factor is duration of use. Many of the adverse effects of drugs are readily apparent only after prolonged use (e.g. dependence); thus, use of nicotine replacement for I month vs 6 months may produce very different risk profiles. 4. Safety and Toxicity of Nicotine Replacement Products 4.1 Nicotine Polacrilex Ad-lib use of the 2mg gum produces blood con- centrations of about 30 to 40% and with 4mg gum 40 to 5096 of those from smoking (Benowitz 1988b; I

~ Risk-Benetit Assessment of tiicotine Preparations ._ I I I I I I I I I I I I Fagerstrom 1988). With fixed dosages, 50 to 100% replacement can be achieved. The minor adverse effects of the gum are mechantcal (sore jaw, air swallowtng. denture adhesion) and pharmacologi- cal (burning throat. hiccups. stomach-ache) (Chris- ten & McDonald 1988: Hughes 1986aJ. Major ad- verse effects (e.g. arrhythmias) have been very rare. Abrupt cessation of polacrilex can precipitate ni- cotine withdrawal symptoms (Hughes 1988a). Among smokers who stop while using the gum. 30 to 40% use the gum beyond the recommended 3 months but only 15 to 20% use gum for more than t year. and these patients use less than 20 mg/day (Hughes 1991: Hughes et al. 1991). 4.2 Transdermal Nicotine High doses of transdermal nicotine (e.g. 21 mg/ day) produce 40 to 50% replacement of nicotine (Fagerstrom et al. 1992: Palmer & Faulds 1992). The most common adverse effect is mild itching and erythema at the site of application. More sev- ere allergic reactions at the site occur in 2 to 6% of smokers. and about 2 to 7% of smokers have to discontinue transdermal nicotine due to adverse effects. Patches differ in how much nicotine is ac- tually in contact with the skin; however, a direct comparison of skin-related or other adverse effects of the different patches has not been reported. Insomnia is another common adverse effect of transdermal nicotine, which can be difficult to as- sess as insomnia is also a symptom of nicotine withdrawal (Hughes et al. 1990). My clinical ex- perience has been that insomnia from withdrawal is characterised by increased awakenings. whereas insomnia from transdermal nicotine is character- ised by delayed onset of sleep. One important feature of the 24-hour patches is that nicotine is continuously delivered whereas with smoking, nicotine is self-administered for only 14 to 18 h/day. Since many cardiovascular effects oc- cur in the early morning hours (Levine et al. 1992), the presence of nicotine during this time may be important; however, the effects of 24- vs 16-hour patches on cardiovascular parameters have not been studied in this regard. Sometimes patients who are receiving little withdrawal relief from transdermal nicotine are tried on higher than normal doses of transdermal nicotine (>21 mg/day) because the dose of nicotine required to suppress withdrawal varies widely across patients. Some of these patients may have mild symptoms of nicotine intoxication. Also, some patients use transdermal nicotine inappropriately and smoke while using transdermal nicotine. This use can produce symptoms of nicotine toxicity as well. Transdermal nicotine has only recently been marketed: thus, the incidence of serious adverse ef- fects (including dependence) is not completely known. In all likelihood, abrupt cessation produces nicotine withdrawal, and some long term use of transdermal nicotine beyond the recommended pe- riod will occur. There are several reasons to believe long term use will be less prevalent than that with polacrilex; e.g. the patch is applied once daily and absorption is slower. In addition. ad lib use of po- lacrilex continues the conditioning of nicotine in- take with relief from stressful situations; i.e. abs- tinent smokers often use nicotine polacrilex when they are anxious, need to concentrate, etc. This continued experience of nicotine relieving anxiety, difficulty concentrating, etc.. probably contributes to the long term use of polacrilex. With transder- mal nicotine, this does not occur since nicotine is present independent of these events. 4.3 Nicotine Nasal Spray Nicotine nasal spray produces about 50% re- placement with a peak at 5 to 10 min (West et al. 1984). Local irritation of the nose. eyes and throat occurs but declines with usage (Jarvis et al. 1987). Long term nasal complications have not been re- ported. Although not yet studied, due to its rapid absorption and need for high frequency of use, the abuse liability and dependence potential of nico- tine nasal spray could be high (Hughes 1988a). 4.4 Nicotine Aerosols and Vapours Cigarette-like rods with nicotine-impregnated plugs have been marketed both as a smoking ces- sation aid (Hajek et al. 1989) and as a cigarette

1 '4 Druq SaJetr •9 ~l/ 1993 1 I I I I I I I I I I I I I I I I I replacement. Some of these have to be vigorously and frequently inhaled to produce even 30% re- placement of blood concentrations. Others pro- duce higher replacement (Russell et al. 1987). The most common adverse effects are throat irritation and coughing. These products also are likely to have abuse liability and dependence potential for the reasons outlined for nicotine nasal spray (Hughes 1988a). 4.5 Other Nicotine Preparations Nicotine tablets for buccal absorption (Belcher et al. 1989) and nicotine toothpicks (Hasenfratz & Battig 1991) have been described but little data on efficacy and safety are available. 5. Benef ts of Nicotine Therapy In many countries, rates of smoking are de- creasing and up to 40% of eversmokers have quit (Fiore et al. 1989). However, it is likely that those stopping are the less dependent smokers. If this is true, then future populations of smokers will be composed of the more highly dependent smokers. Nicotine replacement via polacrilex doubles long term quit rates when used with behaviour therapy (Fagerstrom 1988). Polacrilex appears to be espe- cially beneficial to the more dependent smoker (Fagerstrom & Schneider 1989). Transdermal ni- cotine also doubles long term quit rates: however, transdermal nicotine appears to be effective even when given with only brief physician advice (Fa- gerstrom et al. 1992; Hughes 1992). The absolute increase in long term quit rates with polacrilex or transdermal nicotine is 10 to 30%. 6. Risk-Benefit of Nicotine Therapy Overall, the risks of existing nicotine replace- ment products are quite small compared with the large degree of reversibility of diseases, symptoms and risks that occur with smoking cessation (US Department of Health and Human Services 1990). Perhaps the most widely discussed risk of nicotine replacement is that of dependence (US Depart- ment of Health and Human Services 1988a.b). However, even here we must consider (a) in long term users, blood concentrations of nicotine from transdermal nicotine or polacrilex are approxi- mately one quarter of those from smoking; (b) transdermal nicotine or polacrilex does not pro- duce bolus doses: and (c) transdermal nicotine and polacrilex do not produce tar or carbon monoxide, the substances most directly linked to the cancer and heart disease risks of smoking. 6.1 Risk-Benefit in Special Populations 6.1.1 Pregnancy Many pregnant women who smoke stop soon after finding out they are pregnant (US Depart- ment of Health and Human Services 1980). Those who continue to smoke are likely to be those who are highly dependent on nicotine and so might benefit from nicotine replacement therapy (Benow- itz 1991 b). In addition, most of the harmful effects of smoking occur in the third trimester, thus, ces- sation of smoking in the first or second trimester greatly reduces risk. My opinion is that if there is good evidence that a pregnant smoker has made serious attempts at stopping smoking without suc- cess and shows signs of nicotine dependence (e.g. withdrawal symptoms or high scores on the Fa- gerstrom scale), nicotine replacement via polacri- lex or transdermal nicotine should be considered. If prescribed, nicotine therapy should begin at a lower dose and, if possible, be tapered and stopped before the third trimester. In addition, it should be documented that the patient has been informed of the risks of nicotine replacement and agrees to therapy. 6.1.2 Cardiovascular Diseases Since polacrilex and transdermal nicotine pro- duce substantially lower doses of nicotine in a non- bolus form and do not expose the patient to carbon monoxide, I believe they should be considered for those smokers with cardiovascular diseases who have failed in prior serious attempts and who have signs of nicotine dependence. One study suggests that such an approach is beneficial (Rennard et al.

I Risk-Benetit Assessment of Nicotine Preparations 55 I I I I I I I I I I I 1991). Again, lower doses and informed consent should be used. In addition, such patients should be especial:y cautioned about concurrently using transdermal nicotine or polacrilex and smoking. This recommendation for use of nicotine replace- ment may not be appropriate in some patients im- mediately after myocardial infarction and whose cardiac status is significantly compromised. 6.1.3 Children and the Elderlv How quickly adolescents develop dependence on nicotine is unclear; however, recent studies sug- gest some adolescents have withdrawal symptoms when they attempt cessation (McNeil et al. 1986). My opinion is that if such children have failed se- rious attempts to stop and have withdrawal symp- toms, transdermal nicotine or polacrilex should be considered. A lower dose and parental consent (when indicated) would be appropriate. Both trans- dermal nicotine and polacrilex have been used without extra problems in the elderly (Fagerstrom et al. 1992; Paimer & Faulds 1992). 6.1.4 Temporary Use During Nospitalisation Since many hospitals have gone smoke-free, smokers hospitalised for medical/surgical, psychi- atric or substance abuse therapy are sometimes prescribed transdermal nicotine or polacrilex not as an aid to stop smoking, but rather to ameliorate nicotine withdrawal symptoms (e.g. anxiety and insomnia). Such patients should be especially warned about not smoking while using the pa2ch or gum. Teblt 1. Possible areas of future research on the safety and toxtctty of transdermal nicotine. nicotine polacnlex, nicotine nasal spray and other nicotine preparations Adverse effect profiles of the different transoermal nicotine systems, especially 16 vs 24h patches Acceptability of transdermal nicotine vs nicotine gum vs nicotlne nasal spray vs other nicotine preparabons Abuse liability and dependence potential of nicotine nasal spray, aerosols and vapours Cardiovascular benefit from stopping smoking among long term users of transdermal nrconne and potacrilex vs among tnose who stop vrrthout transdermal nicotine or polacnlex Intrauterine effects of transdermat nicotine and polacnlex vs continued smoking Trials of transdermal rncotine in adolescent smokers ToWability of transdermat nicotine among never- and ex- smoken will be marketed to be used either alone or with transdermal nicotine or polacrilex (Jarvis et al. 1987). These products might be abused by smokers and nonsmokers (Hughes 1988a); thus, their abuse liability should be well established before market- ing, both to educate physicians and to help deter- mine regulations or restrictions around their use. Acknowledgements Preparation of this article was supported in part by Research Scientist Development Award K02-00109 from the National Institute on Drug Abuse. The author thanks Neil Benowitz for this thoughtful review of the manu- script. I I I I I I I 7. Future Research Needs Among the several areas of research needed (table 1), two deserve comment. First, several lines of evidence suggest that nicotine might be a ther- apeutic drug for Alzheimer's. Parkinson's and Tourette's diseases and for ulcerative colitis (New- house & Hughes 1991). Before such trials are un- dertaken, the safety and tolerability of transdermal nicotine in the elderly and young never and ex- smokers is needed. Secondly, it is likely that ni- cotine nasal spray or nicotine aerosols or vapours RtfirtAcu American Psychiatric Association (Eds). Diagnostic and statisti- cal manual of mental disorders. 3rd ed. revised. American Psy- chiatric Association. Washington. 1987 Belcher M. Jarvis MJ. Sutherland G. Nicotine absorption and dependence in an over the counter aid to stopping smoking. British Medical Journal 298: 570. 1989 Benowitz NL Clinical pharmacology of nicotine. Annual Review of Medicine 37: 21-32. 1986 Benowitz N. Toxicity of nicotine: implications with regard to ni- cotine replacement therapy. In Pomerteau & Pomerkau (Eds) Nicotine replacement: a critical evaluation. pp. 187-217, Alan R. t.iss. Inc.. New York. 1988a Benowiu NL Phartnacobpc aspects of cigarette smoking and nieotine addiction. New En{land Journal of Medicine 319: 1318- 1330. 1988b Benowitz NL Central nervous system toxicity of nicotine. In Wald

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