H. Pharmacological Treatment

OBJECTIVE

To facilitate abstinence through provision of pharmacological therapy to treat tobacco dependence.

ANNOTATION

Pharmacological therapy can be divided into nicotine replacement products and non-nicotine products. Every person who answers "no" should be offered pharmacotherapy except when medically contraindicated (See G in the algorithm.) Selection should be based on a review of the risks and benefits for each drug and the person's preference. Appendix 2, Pharmacology, includes a comprehensive review of these drugs. Appendix 3, Treatment/Cost, rates the relative cost of dosing.

DISCUSSION

Understanding the role of NRT and non-NRT prescribing is critical for the PCP/PCM.

NICOTINE REPLACEMENT THERAPY

Tobacco use is maintained by dependence on nicotine. Users often perceive that smoking or chewing tobacco helps them cope with stress and improves their mental alertness.⁸ When tobacco use is stopped, symptoms of nicotine withdrawal become noticeable. The positive reinforcement from tobacco use and the negative effects of nicotine withdrawal become powerful factors impeding cessation from tobacco use. Nicotine replacement therapy may therefore be of benefit in selected persons as an aid to tobacco use cessation.⁹

Four types of nicotine replacement therapy (NRT) products are available in the United States for pharmacological treatment of tobacco dependence. NRT is available as:

1. Transdermal delivery system (patches).
2. Polacrilex resin (gum).
3. Nasal spray.
4. Oral vapor inhaler.

In one large trial, NRT was used safely in combination with bupropion for selected healthy, non-depressed smokers.¹⁰ Continued dependence on nicotine is possible with all four types of NRT.

Selection of the NRT should be based on the person's: level of addiction to tobacco, motivation to quit, and concomitant medical conditions.

1. Nicotine Addiction

The higher the person's level of addiction to nicotine, the more likely he or she is to benefit from NRT as an aid to tobacco cessation. A high level of addiction is indicated in persons who:

1. Uses tobacco products every day.
2. Smokes his or her first cigarette within 30 minutes of arising.
3. Usually inhales more frequently or more deeply.
4. Prefer brands of cigarettes with a nicotine level > 0.9 mg.
5. Finds it difficult to refrain from smoking in forbidden areas.
6. Uses tobacco even when so ill they are confined to bed most of the day.
7. Developed withdrawal symptoms in first week(s) of a prior quit attempt.

2. Motivation to Quit

The higher the motivation to quit, the more likely the benefit from nicotine replacement therapy.Providers should determine the person's motivation to quit before prescribing NRT.^{11, 12}

3. Concomitant Medical Condition

Although there are no absolute contraindications to the use of nicotine replacement therapy, caution should be used with any of following medical conditions.

1. Cardiovascular disease ¾ There are concerns that NRT could cause platelet activation and catecholamine release, adversely affecting persons with myocardial infarction and unstable angina.¹³
   
   
2. Unstable coronary artery disease ¾ NRT is relatively contraindicated in persons with unstable coronary artery disease.
   
   
3. Stable coronary artery disease ¾ NRT can be initiated at intermediate doses with careful monitoring.
   
   
4. Pregnancy ¾ the NRT products are category D, except nicotine polacrilex, which is category X, over the counter (OTC), according to the Food and Drug Administration (FDA) pregnancy category rating. The manufacturer does, however, recommend the same cautions and warnings as the other NRT products. The risk of fetal harm due to nicotine must be weighed against the benefit of abstinence from tobacco.
   
   
5. Miscellaneous conditions ¾ Use of NRT must be carefully assessed and monitored in persons with hyperthyroidism, peptic ulcer, insulin-dependent diabetes mellitus, temporomandibular joint syndrome and certain peripheral vascular disease.

Nicotine from any NRT product may be harmful to children or pets if taken orally

EVIDENCE

a. Proper use of nicotine replacements has shown its effectiveness in helping tobacco users quit. LE = A, SR = IIa Jorenby 1999

b. Appropriate treatment is based on person's motivation to quit. LE = B, SR = I Davis 1998,

Thompson 1998

REFERENCES

⁸ Davis 1998; ⁹ Thompson 1998; ¹⁰ Jorenby 1999; ¹¹ Davis 1998; ¹² Thompson 1998; ¹³ Davis 1998

Proper Use of Nicotine Replacement Therapy

Each of the NRT products currently available has inherent advantages and disadvantages as described below.

1. Nicotine Transdermal (patch)^{14, 15, 16, 17, 18}

Nicotine patches are available from several manufacturers in a variety of strengths. Strengths are expressed in the amount of nicotine delivered over the duration that the patch is in place (16 to 24 hours). Generally, patches are categorized as high dose (22 mg, 21 mg), intermediate dose (15 mg, 14 mg, 11 mg, 10 mg), and low dose (7 mg, 5 mg). To use, a new patch should be placed on a hairless area between the neck and waist or inner arm at the start of each day. Patches should not be occluded. Dosing is scheduled as follows:

Heavy dependence: (>24 cigarettes/day) ¾ High-dose patch once daily for 6 weeks, intermediate patch once daily for 2 weeks, low-dose patch once daily for 2 weeks.

Mild dependence: (< 24 cigarettes/day) ¾ Intermediate-dose patch once daily for 6 weeks, low-dose patch once daily for 2 weeks.

Higher dosages have been reported (see Appendix 2, Pharmacology).

1. Advantages:

   1) The controlled delivery of nicotine produces a constant and predictable blood level, once a steady state is reached. This helps avoid stimulatory effects caused by rapid nicotine delivery and the anticipatory effects caused by self-administration of nicotine gum, nasal spray, or vapor inhaler.

   2) Overdosing is rare.

2. Disadvantages:

   1) Steady-state concentration is not reached until 2 to 3 days after placement of first patch.

   2) Tobacco users equaling fewer than 10 cigarettes a day may lose their tolerance to nicotine and experience light-headedness and nausea.

   3) Up to 50 percent of persons may experience dermatological side effects from the patches, usually mild itching and erythema.

2. Nicotine Polacrilex Resin (gum)^{19, 20}

   Nicotine polacrilex gum is available in 2-mg and 4-mg strengths. The 4-mg strength is used in persons who used tobacco equaling more than 24 cigarettes per day; the 2-mg strength is recommended for persons who used tobacco equal to or less than 24 cigarettes per day.

   Dosing is as follows: One piece of gum every 1 to 2 hours for 6 weeks, taper over 6 weeks. Persons should be instructed to chew the gum slowly until a tingling sensation is felt in the gums. The gum should then be "parked" in the buccal mucosa until the tingling subsides. Alternate slow and intermittent chewing and parking the gum for about 30 minutes. Acidic beverages (e.g. coffee, juice) inhibit the absorption of nicotine and should be avoided.

   1. Advantages:

      1) Allows tobacco users to take an active coping response to nicotine withdrawal symptoms.

      2) Provides plasma nicotine concentrations approximately 30 to 64 percent of pre-cessation levels.

      3) Not associated with as much weight gain as placebo during treatment.

   2. Disadvantages:

      1) Effect reduced by acidic beverages.

      2) Some persons may have difficulty following instruction to "park" the gum and may treat it like regular chewing gum resulting in nausea or gastrointestinal upset.

      3) Sticks to dentures, may dislodge fillings and inlays because of its density.

      4) Temporomandibular joint syndrome is a relative contraindication.

3. Nicotine Nasal Spray^{21, 22}

   Nicotine nasal spray is available as a water-based, metered-dose, mist spray that delivers 0.5 mg of nicotine with each spray. A single dose consists of 1 spray in each nostril. The usual adult dose is 1 to 2 sprays/hour, to a maximum of 5 sprays an hour or 40 sprays a day. Persons should be cautioned not to exceed recommended doses, and to be aware of the potential for dependence that may result from use of this product.

   1. Advantages:

      1) Peak concentrations occur more rapidly than other NRT products (within 15 minutes) resembling the kinetics of nicotine seen with cigarette use.

      2) May be better tolerated by those who have had dermatological effects from the patch or dental side effects from the gum.

   2. Disadvantages:

      1) Higher risk of nicotine dependence because of its rapid onset and user control of nicotine delivery.

      2) Local irritant adverse effects, including nasal and throat irritation, runny nose, sneezing, watery eyes, and cough.

4. Nicotine Oral Vapor Inhaler²³

   Nicotine is available as an oral vapor inhaler delivering 4 mg of nicotine from a porous plug containing 10 mg of nicotine. The cartridge is inserted in a mouthpiece resembling a cigarette before use, and inhaled orally. This action mimics the hand-mouth activities associated with smoking, thereby is a tobacco substitute for tobacco use during abstinence. The usual dose for initial treatment is 6 to 16 cartridges per day for up to 12 weeks, followed by a gradual reduction (if needed) for 6 to 12 weeks. Persons should be told to stop smoking completely before using this product, and not to exceed the recommended maximum dosage (16 mg/day).

   1. Advantages:

      1) Peak plasma concentrations occur in 15 minutes, as seen with nicotine nasal spray.

      2) Need for Hand-mouth action can be substituted with this product.

   2. Disadvantages:

      1) High incidence (about 66 percent) of mouth and throat irritation.

      2) High residual level of nicotine in discarded cartridge (danger to children and pets).

EVIDENCE

a) Nicotine Transdermal Patch LE = A, SR = I Henningfield 1995, Hurt et al. 1997, Greenland et al. 1998, Setter et al. 1998, Dale et al. 1995

b) Nicotine Polacrilex Resin (gum) LE = A, SR = I Lam 1987, Murray 1996

c) Nicotine Nasal Spray LE = A, SR = I Hjalmarson et al. 1994, Hurt et al. 1998

d) Nicotine Oral Vapor Inhaler LE = A, SR = I Tonneson et al. 1993

REFERENCES

¹⁴ Henningfield 1995; ¹⁵ Hurt 1997; ¹⁶ Setter 1998; ¹⁷ Dale et al. 1995; ¹⁸ Greenland 1998;

¹⁹ Lam 1987; ²⁰ Murray et al. 1996; ²¹ Hjalmarson et al. 1994; ²² Hurt et al. 1998; ²³ Tonnesen et al. 1993

NON-NICOTINE THERAPY

The only non-nicotine product currently FDA approved is bupropion SR.²⁴ Bupropion is a non-nicotine aid to tobacco use cessation, initially marketed as an antidepressant. It is chemically unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitor, or other known antidepressant agents. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. The mechanism by which bupropion enhances the ability of persons to abstain from smoking is unknown. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.

There are a number of factors to be considered when considering whether a person desiring help in tobacco cessation would be a candidate for bupropion SR. Among them are:

1. Nicotine dependence.
2. Motivation to quit.
3. Inability or disinclination to use nicotine replacement.
4. Contraindicated drugs or disease states.
   
   

Motivation To Quit

The higher the motivation to quit, the more likely the benefit from therapy with bupropion SR.²⁵

Providers should determine the person's motivation to quit before prescribing bupropion SR.

Inability or Disinclination to Use Nicotine Replacement

Persons who desire to stop using tobacco and are unable to use nicotine due to clinical conditions may be candidates for bupropion SR. Because of its category X rating in pregnancy, it may be preferable to nicotine replacement for pregnant women desiring to abstain from smoking.²⁶

Relative Contraindications, Drugs, or Diseases

Bupropion is contraindicated under the following circumstances:²⁷

1. In persons with a seizure disorder, bupropion can potentially lower the seizure threshold in these persons.
   
   
2. Persons who are predisposed to seizures due to a current or prior diagnosis or bulimia or anorexia nervosa.
   
   
3. Persons taking monoamine oxidase inhibitor (MAOI). At least 14 days should elapse from the last dose of the MAOI to initiation of treatment with bupropion SR.

Bupropion should be used with caution (careful evaluation, monitoring) under the following circumstances:²⁸

1. Persons who are taking a noradrenergic antidepressant agent.
   
   
2. Persons with medical conditions that may predispose them to seizures:
   
   
   1. Severe head trauma.
   2. Central nervous system tumor.
   3. History of seizures.
   4. Abrupt withdrawal from heavy, daily alcohol or other sedatives.
   5. Addiction to opiates, cocaine, or stimulants.
   6. Diabetes treated with oral hypoglycemics or insulin.
      
      
3. Persons with hepatic dysfunction or end stage cirrhosis.

EVIDENCE

LE = A, SR = I Hurt et al. 1997, Jorenby 1999 Hughes et al. 1998

REFERENCES

²⁴ Hurt et al. 1997; ²⁵ Setter 1998; ²⁶ Hughes et al. 1998; ²⁷ Dale et al. 1995 ²⁸ Jorenby 1999

Proper Use of Bupropion SR^{29, 30, 31, 32, 33}

Bupropion should be given for 7 to 12 weeks. The usual dose is 150 mg daily for the first 3 days, then 150 mg twice daily for 7 to 12 weeks. Persons should start one week before quitting smoking and set a definite "quit date" sometime after the start of the second week. Persons should be told to swallow the tablets whole, not crushed or chewed. At the end of seven weeks, the prescriber should assess the person's abstinence and consider whether to continue therapy for a longer period than 7 to 12 weeks.

1. Advantages:
   
   
   1. The only orally administered non-nicotine agent currently approved for smoking cessation.
      
      
   2. Can be started while the person is still smoking without adverse effects.
      
      
   3. Bupropion is nonaddicting and nicotine-free, therefore, no withdrawal symptoms occur after discontinuation.
      
      
2. Disadvantages:
   
   
   1. Potential to lower the seizure threshold in some individuals.

EVIDENCE

LE = A, SR = I Hurt 1997, Setter 1998, Dale 1995

REFERENCES

²⁹ Fiore et al. 1994, ³⁰ Hurt et al. 1997, ³¹ Jorenby et al. 1999, ³² Hughes et al. 1998; ³³ Ferry et al. 1994

FOLLOW-UP

A follow-up visit should be scheduled either in person or via telephone within one to two weeks after the person's quitting date.³⁴ Follow-up contact should be timed to occur soon after the quitting date, preferably during the first week. A second follow-up contact is recommended within the first month. Schedule further follow-up contacts as indicated.³⁵

A personalized approach to supporting the person through the tobacco cessation process includes the following steps:

1. Reinforce the decision to quit.
   
   
2. Provide self-help materials and medication prescriptions/recommendations as indicated.
   
   
3. Establish a periodic follow up plan to see the person through to successful cessation.^{36, 37}

REFERENCES

³⁴ Dale et al. 1995; ³⁵ Fiore et al. 1997; ³⁶ Hurt 1997; ³⁷ Law et al. 1995