1. Nortriptyline, St John’s wort, and glucose, do they help? Paul Aveyard Senior Lecturer Department of Primary Care & General Practice University of Birmingham

2. Odds ratios, relative risks and confidence intervals  OR for NRT is 1.77  The 95% confidence intervals are 1.66 to 1.88  The Cochrane collaboration- Tobacco Addiction Review Group  www.nelh.nhs.uk/cochrane.asp

3. What is nortriptyline?  Tricylic drug  Effects mainly to augment noradrenaline (norepinephrine) transmission in multiple areas of the brain  Anticholinergic  Influences serotonin transmission

4. Antidepressants and smoking cessation  Bupropion discovered by accident  Effectiveness perhaps due to effects on enhancing dopamine levels in the nucleus accumbens  Depression and smoking are linked –Smoking twice as common among those with depression than those without –Depression history, depressive symptoms, or development of depression predict failure of quit attempt

5. SSRIs for smoking cessation  Fluoxetine (Prozac), citalopram (Cipramil), paroxetine (Seroxat)  Recommended 1 st line for depression by NICE  2 trials of fluoxetine vs placebo –Niaura 2002,  OR (95%CI) was 0.98 (0.63-1.53) –Spring 2004  OR (95%CI) was 0.64 (0.34-1.23) –Combined gives 0.86 (0.60-1.23)

6.  Sertraline vs placebo –OR (95%CI) was 0.67 (0.25-1.78)  SSRI + NRT versus placebo + NRT –Fluoxetine OR (95%CI) was 0.88 (0.34- 2.27) –Paroxetine 1.32 (0.62-2.80) and 0.91 (0.41-2.00)  Combined meta-analysis OR (95%CI) is 0.90 (0.68-1.18) and just SSRI vs placebo is 0.83 (0.59-1.17)

7. Hall 1998  Screened 248, enrolled 199 participants  Smoked around 22 cigs/day  FTQ score of 5.6  Mean baseline CO 25 ppm  Participants met weekly with therapist for 12 weeks  3 days on 25mg, 4 days on 50mg, blood test to assess levels, and up to 75mg in week 2 and up to 100mg in week 4. Modal dose was 100mg  Continued medication to week 12, then titrated down  Weekly support from week 4  Quit day week 5

8.  4 dropped out because of s/e in active and 1 in placebo  Abstinence rates at 12 months 24% nortriptyline and 12% placebo OR (95%CI) is 2.3 (1.1-5.0)  Some evidence that blood concentration of nortriptyline related to quitting success, even when compliance controlled  Depressive symptoms reduced on quitting in nortriptyline group but increased in placebo  Drug appeared to work equally well with or without a history of depression  No effect on withdrawal score

9. Prochazka 1998  239 screened, of whom 214 in the study  Smokers >=10 cigs/ day  Excluded those with psychiatric disorder or on contra- indicated medication  2 group sessions prior to quitting and prior to medication starting  3 days on 25mg, then 3 days on 50mg, then 75mg if tolerated for 8 more weeks  Dose adjusted according to blood test 1 week after quitting, 11 days after on 75mg/day  Average 21 cigs/day, CO 25ppm  Full history, examination, ECG

10.  Discontinued medication –Placebo 75% (3% due to adverse effects) –Nortriptyline 61% (9% due to adverse effects)  Side-effects –Dry mouth 64% versus 23% –Dysgeusia 20% versus 8% –GI upset 41% versus 24% –Drowsiness 24% versus 8%

11.  Average Day 1-8 withdrawal scores (0-5 scale) –Craving 2.1 vs 2.8 –Irritable 1.2 vs 1.8 –Anxious 1.2 vs 2.1 –Difficulty concentrating 0.8 vs 1.5 –Restlessness 1.0 vs 1.9 –Insomnia 0.6 vs 1.1 –Drowsiness 0.8 vs 1.1 –Headaches 0.4 vs 0.8  Cessation 15% vs 3% at 6 months

12. Hall 2002  10 cigs/day+  Bupropion versus nortriptyline vs placebo  Same dosing schedule with nortriptyline  178 excluded, 220 randomised  Drop-out due to s/e –8% bupropion –4% nortriptyline –4% placebo  Continuous abstinence at 12 months –16% bupropion –10% nortriptyline –8% placebo  72% on nortriptyline had dry mouth and 32% constipation compared to 33% and 14%

13. Da Costa 2002  236 smokers >=15 cigs/day of which 144 enrolled  Not depressed and not on antidepressants  Full medical history, examination, CXR, ECG  25mg for 1 week then dose escalated by 25mg/ week till 75mg for 6 weeks  6 sessions of cognitive behavioural therapy with a psychiatrist  No apparent quit day, but success if stopped prior to day 35 and maintained abstinence until day 42  Followed up at 3 &6 months from end of therapy also

14.  Persistence with medication –Nortriptyline 10 stopped medication (15%) –Placebo 10 stopped medication (13%)  S/e nortriptyline 5 (7%)  S/e placebo 3 (4%)  Quit rates –End of treatment  Nortriptyline 56%  Placebo 24% – 3 months from end of therapy  Nortriptyline 27%  Placebo 5% –6 months from end of therapy  Nortriptyline 21%  Placebo 5%

16. Summary of effectiveness OR (95%CI)

17. Hall 2004  Smokers >=10 cigs/day  Exclusions related to contra-indications  Five 90-minute group counselling sessions  Nortriptyline or placebo for 12 weeks (same regimen)  Quit day at week 5  NRT patch began at week 5 for 8 weeks, with tapering  At week 12 told whether randomised to either treatment for further 40 weeks or 1 week tapering  Together with 20-30 minute sessions monthly for the rest of the year  FTND 4.6 19 cigs/day

18. 6 months outcome 44% versus 43% MH RR (95%CI) 1.03 (0.73-1.45) 12 month MH RR 1.00 (0.75-1.35)

19.  Withdrawal symptoms measured at 12 weeks (i.e 7 weeks after quit day) –In nortriptyline, withdrawal (Minnesota changed from 7.3 (baseline) to 4.8 (wk12) –In placebo, withdrawal changed from 4.8 (baseline) to 6.5 (12 wks)  Side-effects (assessed weekly by checklist) –Dry mouth (85% vs 40%) –Light-headed (44% vs 22%) –Shaky hands (30% vs 14%) –Constipation (38% vs 15%) –Difficulty urinating (13% vs 2%) –Sexual difficulties (19% vs 2%) –Blurry vision (23% vs 7%)  Stopped using drug due to s/e –Nortriptyline 5% –Placebo 6%

20. Prochazka 2004  Smokers >=10 cigs/day  Excluded 244 people out of 402 for contra-indications  FTND 5.6, 22 cigs/day  Nortriptyline began 14 days before quit day –25mg for 4 days, 50mg for 4 days, then 75mg for 6 days prior to quitting (if tolerated) –10 weeks after quit, then tapered over 2 weeks (14 weeks total)  8 weeks of NRT patch –21mg for 4 weeks, 2 weeks 14mg, 2 weeks 7mg  Weekly one-to-one support for 14 weeks

22. Discontinued drug due to s/e Nortriptyline 13% Placebo 1% Capsules/ day Nortriptyline 2.5 Placebo 3

23.  Sustained abstinence at 6 months –Nortriptyline 23% –Placebo 10% –OR 2.62 (1.06-6.44)

24. SCANAG  900 smokers >=10cigs/day  Using NRT to assist cessation  Using an NHS stop smoking clinic  No exclusions to NRT or nortriptyline  Designed to work in group-based services but some GP practices used

25. The process of running the trial  After person books to attend service gets sent leaflet about the trial  At the first meeting, SCANAG nurse/doctor attended group  Nurse training  Advisor training  10 minutes one-to-one  Medication allocated and sent by registered post

26. Medication  Nortriptyline encapsulated  1 (=25mg) per day for 3 days  2 per day for 4 days  3 a day thereafter  Medicines management

27. Services  South Birmingham, Sandwell, Walsall, Wolverhampton, Coventry, (Warwickshire)  Gwent, Blackwater Valley and Hart PCT, Buckinghamshire, Hertfordshire

28. Dry mouthDrowsiness

29. Blurred visionConstipation

30. Difficulty passing urine Sweating

31. HeadacheInsomnia

32. Irritation Inattention

33. Anxiety Light headed

34. Shaky hands 1 symptom very or extremely troublesome

35. Abstinence over 4 weeks

41. Use of trial medication

42. Use of trial medication in those still quit

46. Quit dayWeek1

47. Week 2 Week 3

48. Week 4

52. 1.11 [0.90; 1.36]

53. Conclusions on nortriptyline  Effective, probably more so than either NRT or bupropion  Not effective when used in combination with NRT  The effects on withdrawal symptoms are modest  Most people will experience a dry mouth  10-15% become constipated  Many will experience initial light-headedness  1 in 10 settling to 1 in 20 will have a troubling s/e  8 out of 10 will persist with the drug  Most will take it in doses shown to be effective  Start the drug 2 weeks before quitting

54. Glucose

55. Jarvik 1998 StudyParticipantsDoseEffect Jarvik 1998 Temporary abstainers ?No reduction in withdrawal

56. Berlin 2005 StudyParticipantsDoseEffect Berlin 2005 Temporary abstainers from 8pm previous night to end of assessment day 32.5g or 75g of glucose drink Small reduction in craving, no change in withdrawal

57. 72 point scale 28 point scale

58. West 1999 StudyParticipantsDoseEffect West 1999 Temporary overnight abstainers 4x3g glucose tablets Reduced cravings

59. How strong is your desire for a cigarette right now? I have a desire for a cigarette right now

60. Harakas 2002 StudyParticipantsDoseEffect Harakas 2002 Temporary overnight abstainers 4x3g glucose tablets No reduction in total withdrawal

61. How strong is your desire for a cigarette right now? I have a desire for a cigarette right now

62. Helmers 1998  Sucrose given to temporary abstainers –40 minutes later measures taken  Total withdrawal symptoms reduced by 1.3 in placebo and 1.9 in sucrose groups (on a 39 point scale)  Drowsiness and anxiety reduced by 0.6 on a 4 point scale StudyParticipantsDoseEffect Helmers 1998 Temporary overnight abstainers 50g sucrose (=fructose + glucose) No effect

63. West 1990 StudyParticipantsDoseEffect West 1990 Real quitters not using medication Ad lib use of many tablets over a week Reduced cravings

64. McRobbie 2004 7 point scale

65. West 1998 StudyParticipantsDoseEffect West 1998 Real quitters after 1 week abstinence on no medication Ad lib use of many tablets over a week (average 40) 0.4 point difference in cravings (on a 15 point scale) West 1998 Real quitters after 1 week abstinence on NRT Ad lib use of many tablets over a week 0.7 point difference in cravings (on a 15 point scale)

66. Jarvick 1998  In real quitters –Placebo group showed a decrease in craving –Glucose group showed an increase in craving

67. Conclusions on craving and withdrawal  Cravings –Inconsistent evidence –Dose effect –Effect apparent in those on no medication –No evidence of reduced cravings on NRT or bupropion  Withdrawal –Very weak evidence of reduced withdrawal symptoms –Some evidence for this in real quitters on bupropion but not NRT

68. Effects on quitting  West 1998- 4 week abstinence –On NRT RR (95%CI) is 1.41 (1.05-1.90) –On placebo is 1.30 (0.93-1.82) –MH combined is 1.36 (1.09-1.70)  West 2006 (unpublished) –At 4 weeks is 1.13 (0.95-1.34) –At 6 months is 1.09 (0.79-1.49)  In those on NRT (28%), bupropion (20%) or both (3%) 6 month quit rates were 18% vs 13%  In those on no medication, 6 month quit rates were 11% vs 14%

69. Conclusions on glucose  May take the edge off craving and withdrawal (evidence stronger in those on no medication or bupropion)  May have a small role in improving quit rates (evidence weak, but stronger in those on NRT and bupropion)  Adjunct advice only

70. St John’s wort

71. Becker et al 2003  RCT 45 smokers  Given NRT one brief counselling session and a self- help manual  Randomised to SJW spray or mint spray  Daily diary of intensity of six withdrawal symptoms  SJW had lower anxiety, restlessness, sleepiness over 2 weeks  Quit rate was 33% in each group at 1 month  Gives RR~ 1.00 (0.44-2.29)

72. Lawvere et al 2005  (Withdrawn abstract)  37 smokers given 900mg SJW/day for 3 months  4 visits and 9 phone calls of behavioural support  Point prevalence ITT quit rate was 24% at 3 months, 19% at 6 months, 11% at 12 months  No significant weight gain  2 stopped taking the drug (1 due to s/e and 1 due to starting other medication)

73. Barnes 2006  28 smokers randomised to either 300mg or 600mg SJW for 3 months when attended pharmacist  Continuous CO validated abstinence was 18% at 3 months and 0% at 12 months

74. Conclusions on SJW  No evidence that it works and should not be recommended  Evidence is insufficient to say it does not work

75. A 2x2 double blind randomised trial to examine the influence of SJW on smoking cessation and chromium on post- cessation weight gain  Explanatory trial, so effort goes into making treatment standardised and tested in ideal conditions  2 weeks pre-cessation treatment  12 weeks thereafter  Randomised to SJW or placebo and chromium or placebo  Outcome assessed at 4 weeks post-cessation  Followed to 6 months  One-to-one behavioural support at visits 2-7  Can use NRT at week 4 (visit 7) onwards  Aiming for 140 participants