Nicotine Replacement Therapy: Patch or Gum?

By:

Group #8
Abigail Ondeck (Psychological Effects) Aman Gulati (Sociology) Daniel Lawler (Intro/Discussion, Efficacy, Compiling) Jennifer Buse (Physiological Effects) Ross Lapkowicz (Calculations and Discussion for Gum) Seth Napierkowski (Calulations and Discussion for Patch) Xingyi Zhao (Dosage and Mechanism of Uptake)

06-323 Heat and Mass Transfer December 10th, 2010

Introduction: Our group was assigned to investigate two different methods of drug delivery for Nicotine Replacement Therapy. We set out to determine whether transfer through gum or patches would be a better option for our company. Our company has developed a new technology that allows for the creation of polymers that bind to nicotine cheaper, so in order to best use this new discovery, we must determine how we will sell the nicotine. To determine which option is best, we must look at not only effectiveness, but also the ethical questions surrounding the two Nicotine Replacement Therapy options. In the paper we will determine the efficiency of the two methods and go over ethical issues including efficacy, physiological effects, psychological effects, sociology, and dosage and mechanism of uptake. After reviewing all of the data we collected and the ethical values we felt were important, we will determine which method of Nicotine Replacement Theory is best and why. To model the mass transfer by method of patch for delivery, we modeled the process as two Semi-Infinite Walls. When accounting for various factors such as diffusivity of the patch and the skin, the area of the patch, and the amount of time the patch is left on, we were able to estimate the diffusion of nicotine into the skin. To model the mass transfer of the gum, we modeled the problem as an Arnold Cell. In this case the factors that effected the final diffusion of nicotine were the length of the dermal layer, the diffusivity of nicotine in saliva, the area of gum interacting, and the amount of time the gum was chewed. After factoring all of these variables and estimating how much nicotine was in the gum, we were able to determine the diffusion of nicotine and the efficiency of the gum at delivering the nicotine in it. Discussion of Solution: After calculating the diffusion of nicotine in the patch and gum and weighing the ethical choices, our group determined that the best method of nicotine delivery for our company is by gum. The fact that patients can put many more patches on the body than pieces of gum in their mouth influenced our decision heavily. That along with the fact that the gum was calculated to give a higher diffusion of nicotine into the body were why we chose the gum option. People can only chew so much gum at a time so the dosage can be controlled in the method that the dosage in a piece of gum could be calculated so an overdose of gum could not be placed in the mouth at one time. However, with the patch, many of them could be placed on the body and cause an over-dose of nicotine. Our company would have to be very careful to avoid lawsuits due to this issue and if the product is known to cause overdoses, the popularity would likely fall even if no legal action is taken. Despite the fact that we chose the gum as our companys method of delivery, the patch does have valuable aspects which may entice our company eventually to expand to providing both products to fit the needs of all of our customers. The most important aspect of the patch is that it is less noticeable and does not have the bad taste that the gum contains. If somebody doesnt want coworkers or family to know that they smoked they can easily put the patch on the skin under their shirt/blouse and nobody would be able to see it. If they were chewing gum all of the time, it may be obvious that the gum is not just regular chewing gum and is in fact nicotine replacement therapy gum. Despite all of this we still believe it would be safer to have NRT gum rather than the patch, despite the bad taste and ability to hide the patch.

The remainder of our paper will discuss the ethical issues we used to determine our choice more in depth and our calculations for the patch and the gum. Here are the calculations we made for the gum and patch options:[1][2][3][4][5][6]

Gum: Using data for Nicorette gum that contains 4 mg of nicotine, our answer was quite comparable. By getting a value of 2.62 mg of nicotine for the gum, our answer was actually slightly under the predicted value for the gum. Typically, the gum is 80-100% effective at getting nicotine into the system. Our value was only 66% efficient in regards to nicotine return. Since Kg is not involved in the calculations, it would not affect the dosage if the value went up or down. However, Dns is directly proportional to the dosage value, while the length, L, is

inversely proportional to the dosage. Physiological effects that would alter the dosage would be how well the nicotine was able to diffuse into the pores of the mouth. This value would be different for most people and would change the dosage that the user receives. [1][2][3][4] Patch: This dosage of 1.455 mg of nicotine compares very favorably with values for normal cigarettes. Light cigarettes typically have a nicotine dosage of 1.0 mg while the heavier cigarettes have dosages around 2.1 mg of nicotine. Increasing the Kp value would cause the dosage of nicotine from the patch to increase, since Kp is directly proportional to 2. Manufacturers would not want to make the Kp value much higher however, because the patch is already supplying the necessary amount of nicotine to the user. Increasing Dns would also cause the dosage to increase, but by a factor of the square root of Dns. Physiological means that could change the dosage is the fact that not everyone's skin is the same. Therefore, the Dab value will be different for almost every person.[5][6] Efficacy: When discussed in terms of health, efficacy is the ability for a product or treatment to help a patient. With all treatments, trials are done to determine if the given product or method is more beneficial to a patient than either the current treatment or than a placebo. Nicotine Replacement Therapy (NRT) is a widely advertised way of aiding people quit smoking by giving them doses of nicotine without the other harmful chemicals that are inhaled through the process of smoking cigarettes. Although widely publicized by advertisements for various patches and gums that are available for over-the-counter treatment, NRT is still in the process of being researched to see how effective the treatment is for aiding people to quit smoking. Research to test NRT was done at the Centre d'Investigations Cliniques at the Hpital Saint Louis in Paris, France. After treatment of over 6000 smokers, a group at the Centre d'Investigations Cliniques found that NRTs protection against relapse declined steadily over time and the risk of relapse after stopping NRT is significant enough that continued use of NRT beyond 6 months of use was recommended [7]. These findings were confirmed by a study done at the Institute of Social and Preventive Medicine in Geneva, Switzerland at the University of Geneva. This study found that most of the cases of relapse from NRT occur during the first or second year and does not continue so long as treatment is repeated [8]. It is apparent from viewing the results of these studies that NRT has the potential to help smokers quit but only because they can find their addiction to nicotine by other means. Whether or not keeping smokers on NRT is better than other methods of quitting assistance is still up for debate. A study was done at Department of Ambulatory Care and Community Medicine at the University Hospital in Lausanne, Switzerland on what methods of assisting smokers to quit smoking work most effectively. This study found that the proper method of treatment depends on how ready the patient was to quit. In cases where the patient was ready to quit NRT was found to have high efficacy with double the success rate of control conditions [9]. Overall the efficacy of NRT seems to be high, but when compared to other options such as psychological counseling and motivational coaching, it is debatable whether NRT is worth it. Because studies have shown that continued use of NRT usually prevents relapse, our group

believes that NRT is an effective method of helping smokers quit however factors such as how committed the patient is to quitting must be considered before the patient starts NRT. Physiological Effect: The psychological effect of smoking is that people, who after smoking for a week or so, become tolerant to the unpleasant effects of nicotine so they can concentrate on the good feelings that nicotine produces physiologically. After smoking for a while, when a person tries to quit, they psychologically break down. They are used to the normal feeling and feel that they have to smoke and maintain that level of nicotine necessary for their well-being.[10] Psychologically, NRT may not be the best option since NRT does not address the psychological effects of a smoking addiction directly. However it does address the addiction at another level after a period of time. After the smoker has stopped smoking, usually after 6 months, the psychological effects of nicotine have stopped since the ex-smoker has now established a new way of life that does not depend on the level of nicotine in his or her blood. It has been shown in a study, that there were no adverse psychological effects on smokers during treatment using NRT.[11] When it comes to self-medication with NRT gum, the patch could be worse. Psychological Effects: There have been numerous studies on the testing of NRT to be sure that it is a safe replacement for nicotine. Before the Food and Drug Administration could approve it, it went through rigorous inspection. The Division of Lung Diseases, National Heart, Lung, and Blood Institute sponsored the studies which was a review of 5,887 patients from 10 clinical centers recruited between 1987-1989.[12] Its purpose was to be sure that this supplement did not cause chronic obstructive pulmonary disease, one of the most common forms of lung disease. The study honed in on gum containing 2mg of nicotine. The side effects were self-reported by the patients every four months over a five year trial period. These are summarized in the table below. NRT users reporting symptoms at first 4-month visit[12] Symptom Men Women Belching Hiccups Indigestion Jaw muscle ache Mouth irritation Mouth ulcers Nausea Throat irritation Other symptoms No symptoms Sample size 1.0 2.8 5.1 1.6 6.2 4.0 1.8 2.2 7.4 73.1 1,797 1.1 3.8 3.9 1.2 6.5 5.3 3.8 2.8 7.0 71.2 1,146

The study also tracked the amount of cardiovascular issues in participants, shown below: Fatal and Nonfatal Cardiovascular Events among 3,332 SI Participants.[12] Cause Hospitalizations Deaths Myocardial infarction Angina Ischemic Heart Disease Congestive heart failure Other CHD Stroke Transient ischemic attack Arrhythmia Pulmonary embolism Hypertension Other CVD Sudden Cardiac 55 6 47 3 2 10 5 12 6 1 40 5 4 3

1 4

The University of North Carolina Greensboro Wellness Center cites the Center for Disease Control and Prevention, American Cancer Society, and the FDA in their discussion of NRT and its addictive qualities.[13] They assure that the risk of becoming addicted to NRT is very small, but when quitting there may be some withdrawal symptoms. This is because the dose of nicotine in NRT is not as high as in cigarettes, but the symptoms are much less than those associated with quitting smoking without the aid of NRT. In order for this, like other drugs, to be encouraged in an ethical manner, the user must be informed of the results of these studies and other studies like it. This way, they know exactly what theyre getting themselves into, and can assess for themselves if the risks are worth it. Sociology: Socioeconomically deprived young smokers have issues to deal with that are not faced by adults trying to achieve the same goal of quitting smoking. Many have the urge to quit, but have tried but failed to stop smoking because of the following reasons. Cheap smuggled cigarettes are easily available to this under aged smokers, typically between the ages of 12 to 16, in this socioeconomic group. As most smokers start at very early age, young smokers have very high chances of making it a lifelong habit which is much harder to quit. For a large proportion of young smokers the problem with quitting is less of nicotine addiction since they had shorter exposure to cigarettes and had low measures of addiction. Other factors such as social pressure contribute more because most of these teens come from families in which at least one parent is also a smoker, or they had peers who smoked. Influence of the people around them who exposed these individuals to cigarettes on a regular basis makes it hard to stay motivated to quit. For this reason his group would respond better to short acting

preparations such as nicotine gum and inhaler rather than the more popularly used patches which give a constant dose of nicotine while it is applied. Despite there being a large population of teenagers that would like to quit smoking, most of the cessation services are targeted only to adults and are the few that cater to young people are also not trained to proved counseling and an NRT schedule that suits their needs. In many cases they also lack means to bear the financial costs of these services when their families either do not know that they smoke, or would not want to take on the costs for them to quit smoking. Young smokers find these cessation services ineffective and rather given into cigarettes after a couple by avoiding to attend counseling services and not continuing with NRT.[14] Dosage and Mechanism of Uptake: According to the equations, the rate of nicotine uptake is a function of the diffusion coefficient of nicotine in the skin, the original density of nicotine in the patch, and the density of nicotine at the body-patch interface, which merely depends on the partition coefficient and the density of nicotine in the patch at this interface. Thus, these three main factors have a large impact on the rate of nicotine uptake in the patch, and despite the fact that the original density of nicotine in the patch is carefully determined by manufacturers, the other two factors can be varied according to which patch design is employed. Firstly, the patch could include permeation enhancers that increase the diffusion coefficient of nicotine in skin by enlarging the pores or activating other transport means. One method manufacturers may use is to add low level of alcohol in the patch to improve skin penetration. However, this may cause side effects such as skin irritation and even seizures. Secondly, as shown in the picture below, the drug reservoir is covered by a selectively permeable membrane to control the rate at which nicotine is delivered, and this carrier layer can be made from a variety of plastics, or even in a matrix type. Thus, the properties of this plastic membrane can not only change the diffusivity of nicotine in the patch, but also the amount of nicotine present in the patch at the interface, and hence the density of nicotine at this interface. Materials, on the other hand, can also bring about skin irritations. Other side effects of using nicotine patch may include headache, stomachache, dizziness, vomiting, etc. [15]

[15]

Very similarly, the rate of nicotine uptake in the gum is affected by the diffusion coefficient of nicotine in the saliva along with the initial concentration of nicotine in the gum, the length of dermal layer, and the concentration of saliva itself. Among all these factors, the diffusion coefficient of nicotine in the saliva could again be varied according to different gum designs by different manufacturers, and currently, there are two strengths available on market, 2 mg and 4 mg. In addition, the rate of nicotine released from the gum is also dependent on how it is chewed. Different from ordinary gums, there is a special instruction for nicotine gumschew slowly until the taste is strong and rest it between cheek and gum, chew again when taste fadesbecause slow chewing can help nicotine being absorbed into the bloodstream from the lining of the mouth. However, if chewed continuously, nicotine can be released too quickly and may be swallowed, thus causing side effects such as throat and stomach irritation, indigestion or hiccups. Other side effect may include jaw pain, throat irritation, increased salivation, heartburn, mouth ulcers, etc.[16]

Endnotes: 1) "Nicorette 10mg patch." <http://www.drugs.com/uk/nicorette-10-mg-patch-spc3329.html> 2) "Nicotine." <http://www.inchem.org/documents/icsc/icsc/eisc0519.htm> 3) "Programmable transdermal drug delivery of nicotine using carbon nanotube membranes." <http://www.pnas.org/content/107/26/11698.full> 4) "Nicotine, tar, and CO content of domestic cigarettes." <http://pw1.netcom.com/~rdavis2/smoke.html> 5) "Determination of nicotine in water by gradient ion chromatography." <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TG8-3TXKR48> 6) "Nicorette." <http://www.nicorette.com/> 7) Medioni, A, I Berlin, and A Mallet. "Increased Risk of Relapse after Stopping Nicotine Replacement Therapies: A Mathematical Modelling Approach." Addiction 2.100 (2005): 247-54. Abstract. PubMed. Web. 3 Dec. 2010. <http://www.ncbi.nlm.nih.gov/pubmed/15679754?dopt=AbstractPlus>. 8) Etter, J F, and J A Stapleton. "Nicotine Replacement Therapy for Long-Term Smoking Cessation: A Meta-Analysis." Tob Control 4.15 (2006): 280-5. Abstract. PubMed. Web. 3 Dec. 2010. <http://www.ncbi.nlm.nih.gov/pubmed/16885576?dopt=AbstractPlus>. 9) Cornuz, J. "Treating Tobacco Use and Dependence in Clinical Practice." Expert Opin Pharmacother 6.7 (2006): 783-92. Abstract. PubMed. Web. 3 Dec. 2010. <http://www.ncbi.nlm.nih.gov/pubmed/16556092?dopt=AbstractPlus>. 10) Smoking Cessation - Nicotine Addiction." Smoking Cessation - Quit Smoking Today. Web. 07 Dec. 2010. <http://www.smokingcessation.org/smoking_cessation_nicotine_addiction.asp>. 11) Steinberg, Michael B., Michelle T. Bover, Donna L. Richardson, Amy C. Scmelzer, Jill M. Williams, and Jonathan Foulds. "Drug and Alcohol Dependence." Elsevier (2010). Web. 7 Dec. 2010. <www.elsevier.com/locate/drugalcdep>. 12) FDA:NRT Safety Meeting Safety Data in the Lung Health Study <http://www.fda.gov/downloads/Drugs/NewsEvents/UCM232145.pdf> 13) Nicotine Replacement Therapy(NRT) University of North Carolina Greensboro Student Health Service Wellness Center <http://www.uncg.edu/shs/wellness/smoking/nrt.php> 14) Roddy E, Romilly N, Challenger A, Lewis S, Britton J: Use of nicotine replacement therapy in socioeconomically deprived young smokers: A community-based pilot randomised control trial. Tobacco Control 2006, 15:373-376. 15) How Products are Made: Nicotine Patch http://www.madehow.com/Volume3/Nicotine-Patch.html 16) Nicotine Gum Netdoctor http://www.netdoctor.co.uk/medicines/100003542.html