2. NICOTINE REPLACEMENT THERAPY IN SMOKING CESSATION SCOTT SLEDGE, MD FEBRUARY 2, 1999

3. CIGARETTE SMOKING RELATED MORTALITY Cigarette Smoking is the single most preventable cause of premature death in the United States. >400,000 deaths in the U.S. / year > 10 million deaths attributed directly to smoking since 1964; about 2 million from lung CA MMWR. Nov 98

4. SMOKING ATTRIBUTABLE HEALTH CARE COSTS: In 1993, estimated at $50 billion –$27 billion for hospitals –$15.5 billion for physician expenditures –$4.9 billion for nursing homes –$1.8 billion for prescription drugs –$900 million for home health care MMWR 94

6. IN 1995... 25% of adults in U.S. - current smokers (47 million adults) Of these, 32 million wanted to quit (68%) And 17 million (45%) had stopped for > one day MMWR. Dec 97

7. INCIDENCE of SMOKING: NORTH CAROLINA 26% of those > 18 years smoke; compared with 23% for all states Gender –30% of males smoke –22% of females smoke

8. CAN PHYSICIANS HELP SOLVE THIS PROBLEM? >70% smokers see MD yearly ~70% report wanting to quit Physicians advice -- an important motivator

9. UNFORTUNATELY... 50% smokers-- report being asked about smoking or urged to quit Fewer report specific advice on quitting

10. OBSTACLES TO HELPING PATIENTS QUIT SMOKING Time constraints A perceived lack of skills to be effective Frustration due to low success rates Belief that smoking cessation is not an important part of professional responsibility

11. METHODS TO HELP PATIENTS STOP SMOKING: HEALTH CARE PROVIDER ADVICE AND FOLLOWUP BEHAVIOR MODIFICATION PROGRAMS PHARMACOTHERAPY ALTERNATIVE THERAPIES (e.g.. ACCUPUNCTURE, HYPNOSIS)

12. NICOTINE REPLACEMENT THERAPY NICOTINE POLACRILEX NICOTINE GUM NICOTINE PATCH NICOTINE NASAL SPRAY NICOTINE INHALER

13. NICOTINE GUM

14. NICOTINE GUM Available in two strengths 2 mg form was approved by the FDA in 1984 and 4 mg form approved in 1992 Both strengths became over the counter in April 1996

15. EFFICACY of NICOTINE GUM Hjalmarson, et al published RCT on effectiveness of 2 mg nicotine gum 205 subjects in smoking cessation clinic randomized to nicotine gum or placebo gum At one year, 29% of nicotine gum subjects were abstinent vs. 16% of the placebo group --JAMA 84

16. HIGHER DOSING OF NICOTINE GUM In 1995, Herrera N, et al showed highly dependent smokers need 4 mg gum Highly dependent smokers given 4 mg gum or 2 mg gum. * Lowly dependent smokers given 2 mg gum or placebo.* *(Randomized at quit phase) -Chest 95

18. AT 2 YEAR FOLLOW-UP... Highly dependent group-- Abstinence rates : – 34% for 4 mg and 16% for 2 mg Lowly dependent group-- Abstinence rates: – 39% for 2 mg and 17 % for placebo -- Chest 95

19. WHAT ABOUT PATIENTS IN A PRIMARY CARE SETTING? Hughes, et al published RCT performed at 2 family practice clinics in suburbs 315 smokers assigned 2 mg gum or placebo Patients shown 13 minute video on gum and instructed to use prn for craving Brief follow-up visit at 1 to 2 weeks -JAMA 89

20. RESULTS AT ONE YEAR: 10% of active gum users passed observer and biochemical verification 7% of placebo users passed observer and biochemical verification NOT STATISTICALLY SIGNIFICANT *31 dropouts and 24 noncontacts counted as smokers

21. PROPER USE OF NICOTINE GUM NICOTINE GUM IS NOT CHEWED LIKE OTHER CHEWING GUM –COMPRESS with teeth until peppery – PARK between the cheek and gum. –REPEAT every minute or so for ~ 30 minutes per dose

22. EATING AND DRINKING: Avoid 15 minutes prior to and during use of the gum Acidic beverages (e.g. coffee, fruit juices) reduce nicotine absorption

23. DOSING: Specify a fixed dosing schedule. > one pack per day begin on 4 mg dose. At least one piece per hour for 1 to 3 mos. MAX = 30 pieces of 2 mg gum/day = 20 pieces of 4 mg gum/day

24. WATCH OUT... It is possible to become addicted to nicotine gum. Not recommended for more than 6 months. Gradual tapering IS recommended

25. ADVERSE EFFECTS THROAT BURNING DIZZINESS NAUSEA HICCUPS ABDOMINAL PAIN JAW ACHE

26. NICOTINE PATCH

27. FIVE FDA-APPROVED TRANSDERMAL PATCHES: Habitrol Nicoderm Nicotrol Nicoderm-CQ Prostep Available in US in December 1991 Nicoderm CQ and Nicotrol-- available over the counter Nicotrol-- delivers nicotine for 16 hours

28. EFFICACY Fiore et al performed meta-analysis of RCTS of four weeks or longer that: – Had biochemical confirmation – Subjects not selected on basis of specific diseases (e.g.. coronary artery disease). - JAMA 94

29. META-ANALYSIS: Seventeen studies with total 5098 pts At 6 months...abstinence rates for active patch 22% vs 9% for placebo Included primary care settings and behavior modification programs. Combined ODDS RATIOS = 3.0 (6 mo.)

30. ANALYSIS ALSO FOUND... 16 hour and 24 hour patch--equally efficacious. Intensive counseling enhanced clinical success, but patch was effective with minimal adjuvant therapy. Extending patch treatment > 8 weeks did not increase efficacy. Weaning patients did not have an added beneficial effect in cessation rate.

31. REGARDING DOSING... Available patches = 5 to 22 mg/day of nicotine Pack per day smoker receives 25 to 40 mg of nicotine/day from cigarettes Will higher patch doses be more effective in heavier smokers?

32. In 1995, Dale et al looked at percentage of nicotine replacement and smoking cessation Subjects randomized to 11-, 22-, or 44- mg doses of patch At one year...higher abstinence rates with the 44 mg patch were not found. BUT 44 mg patch was safe & superior in relieving withdrawal symptoms. -JAMA 1995

33. Current Dosage Recommendations: > 10 cigarettes per day--use highest available dose 10 cigarettes per day or fewer -- start with the mid- range dose Fewer than 5 cigarettes per day probably do not need nicotine replacement.

34. PROPER USE OF THE NICOTINE PATCH On the quit date-- apply to a hairless portion of skin after cleansing with soap and water. Apply new patch daily-- preferably at new site Use > 8 weeks is not proven beneficial, and weaning may be unnecessary.

35. ADVERSE EFFECTS: SKIN IRRITATION ITCHING NAUSEA INSOMNIA ABNORMAL DREAMS

36. NICOTINE NASAL SPRAY

37. NICOTINE NASAL SPRAY Available in the United States in 1996 as a prescription product Designed for rapid delivery of nicotine--mimicking the effects of cigarette smoking

38. EFFICACY Sutherland, et al. published RCT examining nicotine nasal spray in a smoking cessation clinic 227 smokers received 4 weeks of supportive group therapy + active nicotine nasal spray or placebo --Lancet Aug. 92

39. Main end point was biochemically validated complete abstinence from smoking At one year...26% of active group abstinent vs. 10% assigned placebo Greatest advantage in the heaviest smokers Withdrawal symptoms, craving for cigarettes, and weight gain were all reduced by active spray

40. WARNING! Blood nicotine levels achieved are higher and faster than with the patch or gum Approximately 43% of smokers started on the nicotine nasal spray will continue using for 12 months after smoking cessation

41. PROPER USE Instruct the patient on how to prime the pump to ready it for use After priming, patient tilts head back and sprays once in each nostril Do not intentionally inhale or sniff while spraying! (absorption is in the nasal mucosa not the sinuses)

42. DOSING... Each spray delivers 0.5 mg of nicotine (each dose = 1 mg) Recommend 1 to 2 doses per hour with a maximum of 5 doses per hour (40 mg per day max.) Treat for 4 to 6 weeks and then wean over an additional 4 to 6 weeks

43. SIDE EFFECTS Almost all patients report nasal and throat irritation, sneezing, and watery eyes during week 1 Symptoms should diminish over the first week of use If not improving after week 1, consider diseontinuing nasal spray

44. NICOTINE INHALER

45. NICOTINE ORAL INHALER Introduced in mid-1998 Prescription product Intended to mimic the smokers hand- to-mouth ritual

46. EFFICACY A one year RCT conducted by Tonnesen et al. 286 volunteers recruited through a newspaper ad (each smoked 10+ cigarettes/day) Subjects randomly assigned to nicotine inhaler or placebo inhaler --JAMA, March 1993

47. RESULTS... At one year, smoking abstinence rate in the active inhaler group was 15% vs. 5% in the placebo inhaler group Minimal levels of advice and support were used in this study Treatment was well tolerated and no serious adverse effects were reported

48. NICOTINE DELIVERY Each cartridge delivers 4 mg of nicotine About 80 puffs on the inhaler equal nicotine from 8 to 12 puffs on a cigarette Nicotine absorbed in buccal and pharyngeal mucosa -- not the bronchi Nicotine plasma concentrations rise more quickly than with gum (slower nasal spray)

49. DOSING AND USE Use 6 to 16 cartridges per day Frequent, continuous puffing over 20 minutes yields the best effects Recommended duration of treatment is 3 months (max. 6 months)

50. SIDE EFFECTS Most common are irritation in the mouth and throat and coughing Generally improve with use In the Tonneson study, no subjects discontinued the inhaler secondary to side effects

51. SMOKING CESSATION CLINICAL PRACTICE GUIDELINES

52. Published by the Agency for Health Care Policy and Research (AHCPR) in 1996 Approximately 3000 research articles and abstracts were reviewed for appropriateness

53. Inclusion criteria for each article: Concerned a randomized controlled trial Follow-up end point at least 5 months after the quit date Published in English in a peer- reviewed journal between 1975 and 1994

54. Panel Recommendations Address Three Audiences: Primary Care Clinicians Smoking Cessation Specialists Health Care administrators, insurers, and purchasers

55. STRATEGIES FOR IMPLEMENTATION Step1. ASK - Systematically Identify All Tobacco Users at Every Visit Step2. ADVISE - Strongly Urge All Smokers to Quit Step 3. Identify Smokers Willing to Make a Quit Attempt Step 4. ASSIST - Aid the Patient in Quitting Step 5. ARRANGE - Schedule Follow-up Contact

58. In Regard to Nicotine Replacement... Identified as the only pharmacologic therapy proven effective Panel recommended that all patients planning a quit attempt be offered NRT (unless contraindicated)

59. Panel opinion was that the patch was preferable to gum in routine clinical use. Fewer compliance problems Less clinician time and effort to train patients in proper use

60. QUESTIONS YET TO BE ANSWERED

61. Which form of nicotine replacement is the most effective? How effective are nicotine replacement combinations? (e.g. patch and inhaler)

62. CONCLUSIONS Nicotine Replacement Therapy is effective in helping patients to quit smoking At this time, patient preference may be the best guide in choosing a form of nicotine replacement Success rates for smoking cessation remain low even with the best interventions

63. AN UNSUCCESSFUL QUIT ATTEMPT SHOULD BE SEEN AS A LEARNING OPPORTUNITY FOR THE NEXT TIME !

64. SPECIAL THANKS TO RAMON VELEZ, MD AMANDA EBRIGHT, MD

65. HAPPY GROUND HOGS DAY!