Download 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

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