Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 The Cochrane collaboration- Tobacco Addiction Review Group www.nelh.nhs.uk/cochrane.asp What is nortriptyline? Tricylic drug Effects mainly to augment noradrenaline (norepinephrine) transmission in multiple areas of the brain Anticholinergic Influences serotonin transmission 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 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) 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 (0.342.27) – 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) 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 4 dropped out because of s/e in active and 1 in placebo Nortriptyline Dry mouth 78% Light-headed 49% Shaky hands 23% Blurry vision 16% Placebo 33% 22% 11% 6% 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 Prochazka 1998 239 screened, of whom 214 in the study Smokers >=10 cigs/ day Excluded those with psychiatric disorder or on contraindicated 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 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% 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 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% 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 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% Summary of effectiveness OR (95%CI) 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 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) 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% 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 Discontinued drug due to s/e •Nortriptyline 13% •Placebo 1% Capsules/ day •Nortriptyline 2.5 •Placebo 3 Sustained abstinence at 6 months – Nortriptyline 23% – Placebo 10% – OR 2.62 (1.06-6.44) 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 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 Medication Nortriptyline encapsulated 1 (=25mg) per day for 3 days 2 per day for 4 days 3 a day thereafter Medicines management Services South Birmingham, Sandwell, Walsall, Wolverhampton, Coventry, (Warwickshire) Gwent, Blackwater Valley and Hart PCT, Buckinghamshire, Hertfordshire 5 Dry mouth Drowsiness 4 3 2 1 QD Wk1 Wk2 Wk3 Wk4 5 5 Blurred vision 4 3 3 2 2 1 1 QD Wk1 Wk2 Wk3 Constipation 4 Wk4 QD Wk1 Wk2 Wk3 Wk4 5 5 4 4 Difficulty passing urine Sweating 3 3 2 2 1 1 QD Wk1 Wk2 Wk3 Wk4 QD Wk1 Wk2 Wk3 Wk4 5 5 Headache 4 3 3 2 2 1 1 QD Wk1 Wk2 Insomnia 4 Wk3 Wk4 QD Wk1 Wk2 Wk3 Wk4 5 5 Inattention Irritation 4 4 3 3 2 2 1 1 QD Wk1 Wk2 Wk3 Wk4 QD Wk1 Wk2 Wk3 Wk4 5 5 Anxiety 4 3 3 2 2 1 1 QD Wk1 Light headed 4 Wk2 Wk3 Wk4 QD Wk1 Wk2 Wk3 Wk4 5 100 90 1 symptom very or extremely troublesome 80 Shaky hands 4 70 60 3 50 40 30 2 20 10 1 0 1.00 2.00 3.00 4.00 7.00 QD Wk1 Wk2 Wk3 Wk4 100 A 90 B 80 70 % abstinent 60 50 Abstinence over 4 weeks 40 30 20 10 0 QD Wk1 Wk2 Wk3 Wk4 Treatment * Confirmed 4 week abstinence Crosstabulation Treatment A B Total Count % within Treatment Count % within Treatment Count % within Treatment Confirmed 4 week abs tinence Not quit Quit 218 227 49.0% 51.0% 237 219 52.0% 48.0% 455 446 50.5% 49.5% Total 445 100.0% 456 100.0% 901 100.0% Treatment * Self-reported 4 week abstinence Crosstabulation Treatment A B Total Count % within Treatment Count % within Treatment Count % within Treatment Self-reported 4 week abs tinence Not quit Quit 173 272 38.9% 61.1% 191 265 41.9% 58.1% 364 537 40.4% 59.6% Total 445 100.0% 456 100.0% 901 100.0% treatment2 * Continuous abstinence 6 months Crosstabulation treatment2 .00 1.00 Total Count % within treatment2 Count % within treatment2 Count % within treatment2 Continuous abs tinence 6 months Smoker Quitter 338 107 76.0% 24.0% 351 105 77.0% 23.0% 689 212 76.5% 23.5% Total 445 100.0% 456 100.0% 901 100.0% treatment2 * Continuous abstinence 6 months * dependent Crosstabulation dependent FTND 0-6 treatment2 .00 1.00 Total FTND 7-10 treatment2 .00 1.00 Total Count % within treatment2 Count % within treatment2 Count % within treatment2 Count % within treatment2 Count % within treatment2 Count % within treatment2 Continuous abs tinence 6 months Smoker Quitter 142 65 68.6% 31.4% 137 69 66.5% 33.5% 279 134 67.6% 32.4% 85 20 81.0% 19.0% 78 17 82.1% 17.9% 163 37 81.5% 18.5% Total 207 100.0% 206 100.0% 413 100.0% 105 100.0% 95 100.0% 200 100.0% treatment2 * Continuous abstinence 6 months * cigpdaycat Crosstabulation cigpdaycat 10-19 treatment2 .00 1.00 Total 20+ treatment2 .00 1.00 Total Count % within treatment2 Count % within treatment2 Count % within treatment2 Count % within treatment2 Count % within treatment2 Count % within treatment2 Continuous abs tinence 6 months Smoker Quitter 64 32 66.7% 33.3% 50 35 58.8% 41.2% 114 67 63.0% 37.0% 166 53 75.8% 24.2% 166 52 76.1% 23.9% 332 105 76.0% 24.0% Total 96 100.0% 85 100.0% 181 100.0% 219 100.0% 218 100.0% 437 100.0% 100 90 A B 80 % using medication 70 60 50 40 30 Use of trial medication 20 10 0 QD Wk1 Wk2 Wk3 Wk4 100 90 A B 80 % using medication 70 60 50 40 30 20 Use of trial medication in those still quit 10 0 QD Wk1 Wk2 Wk3 Wk4 Crosstab Treatment A B Total Count % within Treatment Count % within Treatment Count % within Treatment Confirmed 4 week abs tinence Not quit Quit 78 164 32.2% 67.8% 72 166 30.3% 69.7% 150 330 31.3% 68.8% Total 242 100.0% 238 100.0% 480 100.0% Crosstab Treatment A B Total Count % within Treatment Count % within Treatment Count % within Treatment Self-reported 4 week abs tinence Not quit Quit 50 192 20.7% 79.3% 47 191 19.7% 80.3% 97 383 20.2% 79.8% Total 242 100.0% 238 100.0% 480 100.0% Treatment * Continuous abstinence 6 months Crosstabulation Treatment A B Total Count % within Treatment Count % within Treatment Count % within Treatment Continuous abs tinence 6 months Smoker Quitter 156 86 64.5% 35.5% 162 76 68.1% 31.9% 318 162 66.3% 33.8% Total 242 100.0% 238 100.0% 480 100.0% Quit day Week1 100% 100% 90% 90% 80% 80% 70% 70% 1 2 3 60% 50% 50% 40% 40% 30% 30% 20% 20% 10% 10% 0% 0% A 1 2 3 60% B A B Week 2 Week 3 100% 100% 90% 90% 80% 80% 70% 70% 60% 1 2 60% 3 50% 50% 40% 40% 30% 30% 20% 20% 10% 10% 0% 0% A B 1 2 3 A B Week 4 100% 90% 80% 70% 60% 1 2 3 50% 40% 30% 20% 10% 0% A B 4 4 3 3 A A B 2 1 0 QD -1 Wk1 Wk2 Wk3 Wk4 Change in anxiety score Change in depression score 2 B 1 0 QD -1 -2 -2 -3 -3 -4 -4 Wk1 Wk2 Wk3 Wk4 4 4 A B 3 A 3 B 2 1 0 QD -1 Wk1 Wk2 Wk3 Wk4 Change in irritable score Change in hungry score 2 1 0 QD -1 -2 -2 -3 -3 -4 -4 Wk1 Wk2 Wk3 Wk4 Change in poor concentration score 2 1 0 QD -1 Wk1 Wk2 Wk3 Wk4 Change in poor sleep score 4 4 3 3 B -1 -2 -2 -3 -3 -4 -4 A A B 2 1 0 QD Wk1 Wk2 Wk3 Wk4 1.11 [0.90; 1.36] 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 Glucose Jarvik 1998 Study Participants Dose Effect Jarvik 1998 Temporary abstainers ? No reduction in withdrawal Berlin 2005 Study Participants Dose Effect 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 72 point scale 28 point scale West 1999 Study Participants Dose Effect West 1999 Temporary overnight abstainers 4x3g glucose tablets Reduced cravings How strong is your desire for a cigarette right now? I have a desire for a cigarette right now Harakas 2002 Study Participants Dose Effect Harakas 2002 Temporary overnight abstainers 4x3g glucose tablets No reduction in total withdrawal How strong is your desire for a cigarette right now? I have a desire for a cigarette right now Helmers 1998 Study Participants Dose Effect Helmers 1998 Temporary overnight abstainers 50g sucrose (=fructose + glucose) No effect 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 West 1990 Study Participants Dose Effect West 1990 Real quitters not using medication Ad lib use of many tablets over a week Reduced cravings McRobbie 2004 7 point scale West 1998 Study Participants Dose Effect 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) Jarvick 1998 In real quitters – Placebo group showed a decrease in craving – Glucose group showed an increase in craving 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 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% 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 St John’s wort Becker et al 2003 RCT 45 smokers Given NRT one brief counselling session and a selfhelp 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) 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) 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 Conclusions on SJW No evidence that it works and should not be recommended Evidence is insufficient to say it does not work A 2x2 double blind randomised trial to examine the influence of SJW on smoking cessation and chromium on postcessation 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