nortriptyline, st john’s wort, and glucose, do they help? paul aveyard senior lecturer department...

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%

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

QD Wk1 Wk2 Wk3 Wk4

1

2

3

4

5

Dry mouth Drowsiness

QD Wk1 Wk2 Wk3 Wk4

1

2

3

4

5

Blurred vision

QD Wk1 Wk2 Wk3 Wk4

1

2

3

4

5

Constipation

QD Wk1 Wk2 Wk3 Wk4

1

2

3

4

5

Difficulty passing urine

QD Wk1 Wk2 Wk3 Wk4

1

2

3

4

5

Sweating

QD Wk1 Wk2 Wk3 Wk4

1

2

3

4

5

Headache

QD Wk1 Wk2 Wk3 Wk4

1

2

3

4

5

Insomnia

QD Wk1 Wk2 Wk3 Wk4

1

2

3

4

5

Irritation

QD Wk1 Wk2 Wk3 Wk4

1

2

3

4

5

Inattention

QD Wk1 Wk2 Wk3 Wk4

1

2

3

4

5

Anxiety

QD Wk1 Wk2 Wk3 Wk4

1

2

3

4

5

Light headed

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

0

10

20

30

40

50

60

70

80

90

100

QD Wk1 Wk2 Wk3 Wk4

% a

bstin

ent

A

B

Abstinence over 4 weeks

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


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


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


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

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

A B

1 2 3

Week 4

-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

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 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

72 point scale

28 point scale

West 1999Study 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


Harakas 2002


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

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


Helmers 1998


50g sucrose (=fructose + glucose)

No 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

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 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

nortriptyline, st john’s wort, and glucose, do they help? paul aveyard senior lecturer department...

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