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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 (0.34-
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)
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
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
Nortriptyline Placebo Dry mouth 78% 33% Light-headed 49% 22% Shaky hands 23% 11% Blurry vision 16% 6%
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
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%
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
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
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
1.00 2.00 3.00 4.00 7.00
1
2
3
4
5
Shaky hands
QD Wk1 Wk2 Wk3 Wk4
0
10
20
30
40
50
60
70
80
90
100
1 symptom very or extremely troublesome
Treatment * Confirmed 4 week abstinence Crosstabulation
218 227 445
49.0% 51.0% 100.0%
237 219 456
52.0% 48.0% 100.0%
455 446 901
50.5% 49.5% 100.0%
Count
% within Treatment
Count
% within Treatment
Count
% within Treatment
A
B
Treatment
Total
Not quit Quit
Confirmed 4 weekabstinence
Total
Treatment * Self-reported 4 week abstinence Crosstabulation
173 272 445
38.9% 61.1% 100.0%
191 265 456
41.9% 58.1% 100.0%
364 537 901
40.4% 59.6% 100.0%
Count
% within Treatment
Count
% within Treatment
Count
% within Treatment
A
B
Treatment
Total
Not quit Quit
Self-reported 4 weekabstinence
Total
treatment2 * Continuous abstinence 6 months Crosstabulation
338 107 445
76.0% 24.0% 100.0%
351 105 456
77.0% 23.0% 100.0%
689 212 901
76.5% 23.5% 100.0%
Count
% within treatment2
Count
% within treatment2
Count
% within treatment2
.00
1.00
treatment2
Total
Smoker Quitter
Continuousabstinence 6 months
Total
treatment2 * Continuous abstinence 6 months * dependent Crosstabulation
142 65 207
68.6% 31.4% 100.0%
137 69 206
66.5% 33.5% 100.0%
279 134 413
67.6% 32.4% 100.0%
85 20 105
81.0% 19.0% 100.0%
78 17 95
82.1% 17.9% 100.0%
163 37 200
81.5% 18.5% 100.0%
Count
% within treatment2
Count
% within treatment2
Count
% within treatment2
Count
% within treatment2
Count
% within treatment2
Count
% within treatment2
.00
1.00
treatment2
Total
.00
1.00
treatment2
Total
dependentFTND 0-6
FTND 7-10
Smoker Quitter
Continuousabstinence 6 months
Total
treatment2 * Continuous abstinence 6 months * cigpdaycat Crosstabulation
64 32 96
66.7% 33.3% 100.0%
50 35 85
58.8% 41.2% 100.0%
114 67 181
63.0% 37.0% 100.0%
166 53 219
75.8% 24.2% 100.0%
166 52 218
76.1% 23.9% 100.0%
332 105 437
76.0% 24.0% 100.0%
Count
% within treatment2
Count
% within treatment2
Count
% within treatment2
Count
% within treatment2
Count
% within treatment2
Count
% within treatment2
.00
1.00
treatment2
Total
.00
1.00
treatment2
Total
cigpdaycat10-19
20+
Smoker Quitter
Continuousabstinence 6 months
Total
0
10
20
30
40
50
60
70
80
90
100
QD Wk1 Wk2 Wk3 Wk4
% u
sing
med
icat
ion
A B
Use of trial medication
0
10
20
30
40
50
60
70
80
90
100
QD Wk1 Wk2 Wk3 Wk4
% u
sing
med
icat
ion
A B
Use of trial medication in those still quit
Crosstab
78 164 242
32.2% 67.8% 100.0%
72 166 238
30.3% 69.7% 100.0%
150 330 480
31.3% 68.8% 100.0%
Count
% within Treatment
Count
% within Treatment
Count
% within Treatment
A
B
Treatment
Total
Not quit Quit
Confirmed 4 weekabstinence
Total
Crosstab
50 192 242
20.7% 79.3% 100.0%
47 191 238
19.7% 80.3% 100.0%
97 383 480
20.2% 79.8% 100.0%
Count
% within Treatment
Count
% within Treatment
Count
% within Treatment
A
B
Treatment
Total
Not quit Quit
Self-reported 4 weekabstinence
Total
Treatment * Continuous abstinence 6 months Crosstabulation
156 86 242
64.5% 35.5% 100.0%
162 76 238
68.1% 31.9% 100.0%
318 162 480
66.3% 33.8% 100.0%
Count
% within Treatment
Count
% within Treatment
Count
% within Treatment
A
B
Treatment
Total
Smoker Quitter
Continuousabstinence 6 months
Total
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
A B
1 2 3
Quit day
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
A B
1 2 3
Week1
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
A B
1 2 3
Week 2
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
A B
1 2 3
Week 3
-4
-3
-2
-1
0
1
2
3
4
QD Wk1 Wk2 Wk3 Wk4
Chang
e in de
pressi
on sco
re
A
B
-4
-3
-2
-1
0
1
2
3
4
QD Wk1 Wk2 Wk3 Wk4
Chang
e in an
xiety s
core
A
B
-4
-3
-2
-1
0
1
2
3
4
QD Wk1 Wk2 Wk3 Wk4
Chang
e in hu
ngry s
core
A
B
-4
-3
-2
-1
0
1
2
3
4
QD Wk1 Wk2 Wk3 Wk4
Chang
e in irr
itable s
core
A
B
-4
-3
-2
-1
0
1
2
3
4
QD Wk1 Wk2 Wk3 Wk4
Chang
e in po
or conc
entrati
on sco
re
A
B
-4
-3
-2
-1
0
1
2
3
4
QD Wk1 Wk2 Wk3 Wk4
Chang
e in po
or slee
p scor
e
A
B
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
Jarvik 1998
Study Participants Dose Effect
Jarvik 1998
Temporary abstainers
? No reduction in withdrawal
Berlin 2005Study 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
West 1999Study Participants Dose Effect
West 1999
Temporary overnight abstainers
4x3g glucose tablets
Reduced cravings
Harakas 2002
Study Participants Dose Effect
Harakas 2002
Temporary overnight abstainers
4x3g glucose tablets
No reduction in total withdrawal
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
Study Participants Dose Effect
Helmers 1998
Temporary overnight abstainers
50g sucrose (=fructose + glucose)
No effect
West 1990Study Participants Dose Effect
West 1990
Real quitters not using medication
Ad lib use of many tablets over a week
Reduced cravings
West 1998Study 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
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)
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 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