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Nortriptyline, St John’s wort, and glucose, do they help?

Nortriptyline, St John’s wort, and glucose, do they help?. Paul Aveyard Senior Lecturer Department of Primary Care & General Practice University of Birmingham. Odds ratios, relative risks and confidence intervals. OR for NRT is 1.77 The 95% confidence intervals are 1.66 to 1.88

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Nortriptyline, St John’s wort, and glucose, do they help?

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  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 1st 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%

  15. Summary of effectiveness OR (95%CI)

  16. 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

  17. 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)

  18. 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%

  19. 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

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

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

  22. 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

  23. 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

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

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

  26. Dry mouth Drowsiness

  27. Blurred vision Constipation

  28. Difficulty passing urine Sweating

  29. Headache Insomnia

  30. Inattention Irritation

  31. Anxiety Light headed

  32. 1 symptom very or extremely troublesome Shaky hands

  33. Abstinence over 4 weeks

  34. Use of trial medication

  35. Use of trial medication in those still quit

  36. Quit day Week1

  37. Week 2 Week 3

  38. Week 4

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