Brief communication

Sibutramine does not worsen sleep apnea syndrome: a randomized

double-blind placebo-controlled study

Denis Martinez*, Bibiana Ribeiro Basile

Sleep Laboratory, Federal University of Rio Grande do Sul (UFRGS), Santa Casa Hospital Complex, Porto Alegre, RS, Brazil

Received 8 November 2004; received in revised form 28 January 2005; accepted 1 February 2005

Abstract

Background: As any drug acting on the central nervous system, sibutramine might worsen obstructive sleep apnea–hypopnea syndrome

(OSAHS). This study aims to assess the risk of administering sibutramine to patients with OSAHS.

Methods: We screened male, symptomatic OSAHS patients who presented consecutively at the sleep clinic. Twenty-one subjects were

included, aged between 30 and 60 years, body mass index between 25 and 35 kg/m2 and apnea–hypopnea index (AHI) greater than 10 AH/h.

Intervention was administration of 15 mg sibutramine (SB) or placebo (PL), at bedtime, for 1 month. Each patient underwent overnight

polysomnograms both before entering the study and after 1 month. Outcome measures were AHI and sleep efficiency (SE).

Results: Two patients withdrew prematurely, one due to headache, a possible side effect. Results are from 10 patients in the SB group and

nine in the PL group. No significant differences were seen in any of the groups before or after treatment in measures of SE, respiratory

disturbance, body weight, blood pressure, cardiac or respiratory frequency. Significant reduction occurred in the amount of REM sleep, from

19 to 13% (PZ0.04) in SB group and in Epworth sleepiness score in PL and SB groups.

Conclusion: The results indicate that sibutramine does not worsen sleep or breathing during sleep in patients with OSAHS.

q 2005 Published by Elsevier B.V.

Keywords: Sleep; Sleep apnea syndrome; Obstructive sleep apnea; Sibutramine; Obesity; Drug adverse effects; Anti-obesity agents; Drug safety

1. Introduction

Several drugs that act on the central nervous system

(CNS) may exacerbate obstructive sleep apnea–hypopnea

syndrome (OSAHS) [1,2]. Sedatives [3] and ethanol [4,5],

even in trivial doses [6], worsen the respiratory disturbance.

Anti-obesity medications act on the CNS and have unknown

effects on sleep-disordered breathing.

Sibutramine, an anti-obesity agent, acts centrally and

inhibits serotonin and noradrenaline reuptake [7]. Its

known side effects include headaches, dry mouth, insom-

nia, and constipation [8]. At least the first three are

recognized symptoms of OSAHS and, therefore, what seem

to be side effects may be warning signs arising due to

worsening of preexistent non-symptomatic sleep-disor-

dered breathing.

1389-9457/$ - see front matter q 2005 Published by Elsevier B.V.

doi:10.1016/j.sleep.2005.02.003

* Corresponding author. Tel.: C55 51 3022 2282; fax: C51 3022 2423.

E-mail address: denis@sono.com.br (D. Martinez).

Due to its noradrenergic effects, sibutramine may trigger

systemic arterial hypertension and arrhythmias. Considering

the high percentage of missed OSAHS diagnoses [9], one

can infer that physicians who prescribe drugs for the

treatment of obesity seldom exclude the presence of

OSAHS before commencing treatment. There is clearly a

need for the assessment of the safety profile of anti-obesity

drugs in OSAHS.

Since sibutramine is the leading anti-obesity drug, it seems

prudent to assess its safety. To evaluate the potential risks of

worsening OSAHS or causing insomnia when administering

sibutramine to patients with undiagnosed OSAHS, we

conducted a randomized double-blind, placebo-controlled

trial of sibutramine in 21 patients with OSAHS.

2. Methods

This protocol was approved by the medical ethics

committee of the Santa Casa Hospital Complex of Porto

Alegre and conducted according to the Helsinki Declaration

of 1975 and guidelines from the Brazilian Ministry of Health.

Sleep Medicine 6 (2005) 467–470

www.elsevier.com/locate/sleep

D. Martinez, B.R. Basile / Sleep Medicine 6 (2005) 467–470468

2.1. Patients

We selected 21 male patients who presented consecu-

tively at the sleep clinic with symptoms characteristic of

OSAHS and who gave written informed consent to

participate in the study after full explanation of the

procedures. Inclusion criteria were the following: age

between 30 and 60 years, BMI between 25 and 35 kg/m2,

and an apnea–hypopnea index (AHI) between 10 and 50

apneas–hypopneas per hour. Patients were excluded from

the study and treated immediately with CPAP if (1) they

reported sleepiness while driving or that could be

otherwise dangerous; (2) their arterial oxygen saturation

either fell below 60% or remained below 75% for more

than 5 min; (3) polysomnography (PSG) disclosed some

other significant sleep disorder, for example, difficulty

initiating and/or maintaining sleep with a sleep efficiency

below 80% or a periodic limb movement index greater

than 5; or (4) diastolic blood pressure greater than

105 mmHg. Women were not included to avoid effects of

cyclic hormonal changes on sleep and breathing during

sleep, as well as concerns about pregnancy, menopause,

and irregular menstrual cycles. We excluded patients

regularly taking any CNS-active, respiratory or cardio-

vascular medication, and those with epilepsy, cardiac

disease or any medical or psychiatric illness, acute or

chronic, that could represent a risk for the patient, could

influence the course of OSAHS or is contraindicated for

use with sibutramine.

2.2. Design

The effect of 15 mg sibutramine taken orally at bedtime

for 1 month was investigated in a double-blind, randomized

placebo-controlled trial. The outcome measures were AHI

and sleep efficiency (SE). Patients who fulfilled inclusion

and exclusion criteria were assigned a consecutive study

number. The study medication and placebo capsules were

produced and blinded by personnel at the Brazilian

Research Department of Abbott Laboratories; a randomiz-

ation list was produced using blocks of four. We received 24

numbered boxes of medication, sibutramine (SB) or placebo

(PL), and the code was divulged only at the end of the study.

Patients were informed of the nature of the study and signed

an informed consent form. They were also made aware of

the anti-obesity effects of the drug. To maximize the

potential effects on sleep, treatment medication was taken at

bedtime. Technicians monitoring patients at night could

have been informed by the patients that the second PSG took

place during treatment. Although technicians scoring the

second study may have been aware that there was a first

study, they had no access to the previous results. All

technicians and personnel involved were blinded to study

medication.

2.3. Clinical assessments

During the first office visit, a medical history was taken

and routine physical and laboratory examinations were

performed. Patients filled out the Epworth sleepiness scale.

Blood pressure was measured in the supine position after at

least 10 min rest. After PSG, if the inclusion criteria were

fulfilled, patients were invited to participate in the study. In

accepting, they agreed to return weekly for a brief

assessment of side effects, and measurement of weight,

blood pressure, pulse and respiratory rate so that potential

complications would not go unnoticed. Drug compliance

was assessed by the return of the empty blisters every week

at the clinic visit. Patients filled out a daily sleep log that

was returned weekly. This sleep log was used in our

laboratory to record sleep habits and symptoms using a

visual analog scale to record bedtime and wake-up time

during weekdays and weekends, daytime napping, snoring,

and tiredness. Epworth sleepiness scale was repeated

weekly. Patients were instructed to maintain their usual

nutritional habits throughout the study period.

2.4. Polysomnography

Two overnight polysomnographic studies were per-

formed on all patients: one before entering the study and

one on the 30th day of medication. We employed a Morfeu

polysomnography system (Dolsch, Brazil). The polysomno-

graphic data were recorded from 23:00 to 7:00 h. The

following variables were recorded: electroencephalography

(C3/A2, C4/A1), electrooculography, electromyography

(submental region and anterior tibialis muscles), electro-

cardiography, thoracic and abdominal movements by

respiratory inductance plethysmography (Respitrace, AMI,

NY), and pulse (Ohmeda, Englewood, NJ).

Sleep was staged visually on the computer monitor

according to the standard criteria of Rechtschaffen and

Kales [10], except that we identified the delta wave strictly

by the frequency, without rigorously following the 75 mV

amplitude criterion. Sleep efficiency was calculated as

percentage of total time asleep divided by total time in bed.

Respiratory disturbances were identified visually, and their

number and duration were recorded with the help of

software tools. Apnea was defined as a reduction of

Respitrace tidal volume below 10% of baseline of the sum

signal, calibrated by isovolume maneuver, for at least 10 s.

Hypopnea was defined as a reduction of the tidal volume

below 50% of baseline for at least 10 s, followed by a

transient arousal with or without desaturation. Respiratory

events without arousal were not considered sleep oximetry

disordered breathing.

2.5. Statistical analysis

The results are expressed as meanGSD. We employed a

paired t-test to compare the means of the variables before

D. Martinez, B.R. Basile / Sleep Medicine 6 (2005) 467–470 469

and after treatment, and an independent sample t-test to

compare the means of the variables between the two groups,

placebo and sibutramine (PL and SB), before treatment to

verify the appropriate randomization of the sample. We did

not account for multiple testing and P!0.05 was considered

statistically significant.

3. Results

From October 2000 to August 2001, we screened 43

eligible patients; 21 met the inclusion criteria and were

entered into the study. Two patients in the SB group

withdrew prematurely; one due to the return of a past

chronic headache during the first week of the study,

another due to his wife’s concerns about delaying

treatment. Randomization of the patients created two

similar groups: 9 patients in the PL group and 10

patients in the SB group. There was no significant

difference in anthropometric measurements between the

two groups before treatment.

On the second PSG, after 30 days of treatment, AHI was

virtually unchanged in both groups; sleep efficiency

increased in the PL group and decreased from 92 to 89%

in the SB group without reaching significance. Only two

patients in the SB group showed SE below 85% after SB.

Besides AHI and SE, most PSG variables, including

measures of sleep architecture and respiratory disturbance

(Table 1), were similar before and after medication or

placebo. Amount of REM sleep, however, was significantly

reduced, only in the SB group, from 19 to 13% of sleep time

(PZ0.04).

In the SB group, three patients reported consuming

alcohol once or twice a week and in a fourth case the intake

was daily. One patient in the PL group reported minor

alcohol consumption. The PSG results did not differ

between these five patients and the other patients studied.

Interestingly, however, all four patients given SB who

reported alcohol consumption during the study also showed

an increase in AHI from 26G10 to 36G10 AH/h (PZ0.051), with the largest increase seen in patient SB2 who

reported drinking daily. The drinker in the PL group (patient

PL2) did not exhibit any change in AHI.

Table 1

Polysomnographic data before and after treatment

% Sleep

efficiency

Movement

arousals

% Slow wave

sleep

% RE

sleep

Placebo Before After Before After Before After Befo

MeanGsd 89G5 92G3 203G74 206G91 13G4 13G2 16G

P 0.14 0.89 0.88

Sibutramine Before After Before After Before After Befo

meanGsd 92G2 87G6 204G55 185G86 14G5 16G4 19G

P 0.16* 0.08 0.77* 0.84 0.36* 0.88 0.42*

AHZApneaChypopnea; AHIZapneaChypopnea index; * Pre-treatment difference b

Following treatment, changes in weight, blood pressure,

and respiratory frequency were minimal and non-significant

in both treatment groups. We observed a significant increase

in pulse rate in the SB group, from 76 bpm at baseline to

84 bpm at Day 30 (PZ0.04).

Before treatment, three patients in the PL group and

two in the SB group had abnormal blood pressure

(systolic blood pressure equal to or above 140 mmHg or

diastolic pressure equal to or above 90 mmHg). Blood

pressure increased in four SB patients, reaching abnormal

values in two, from 115/75 to 135/95 mmHg and from

120/80 to 155/95 mmHg. Arterial blood pressure also

increased in four patients in the PL group without

reaching abnormal levels.

The answers to the questionnaires showed a significant

reduction in the Epworth sleepiness score from 11 to 6 in

both groups, PL and SB.

4. Discussion

This short-term study indicates that sibutramine does not

affect OSAHS patients in a clinically significant fashion.

The drug, however, is indicated for long-term management

of obesity and follow-up studies may be required before

concluding on the safety of the drug regarding long-term

side effects on sleep and breathing during sleep.

The fact that in the present study no significant effect on

weight was observed is probably due to the short duration

combined with the lack of advice regarding diet.

Sibutramine is usually prescribed to be taken in the

morning. In this study, it was taken at bedtime to

maximize the effects of the drug on sleep what, in part,

compensates for the small sample size. The absence of

insomnia as result of taking sibutramine at night is

expected in hypersomnolent patients, but cannot be

generalized to other populations.

It has been shown in the literature that hypertensive

patients receiving 10 or 15 mg of sibutramine present a

decrease in blood pressure [11,12]. Normal subjects present

a 2–3 mmHg elevation of blood pressure [8]. In the present

study, the changes in blood pressure were similar to what

has been reported previously in the literature and confirms,

M AHI

(AH/hour)

AH mean

duration (sec)

Lowest

SaO2 (%)

re After Before After Before After Before After

7 18G5 28G12 28G14 22G5 24G8 79G10 81G6

0.33 0.96 0.20 0.33

re After Before After Before After Before After

4 13G6 28G8 27G11 26G6 26G4 79G5 84G4

0.04 0.58* 0.46 0.09* 0.61 0.97* 0.05

etween placebo and sibutramine groups.

D. Martinez, B.R. Basile / Sleep Medicine 6 (2005) 467–470470

together with the increase in pulse rate, the adrenergic

stimulation by sibutramine. It is, therefore, prudent to

measure frequently arterial blood pressure and assess the

risk imposed to patients taking sibutramine.

One could argue that the size of the sample was too

small, not lending enough evidence to support the

conclusion that sibutramine is safe. The differences

observed in the variables analyzed, however, are trivial

and clinically irrelevant. For example, the decrease of

2 mmHg in diastolic blood pressure and the reduction of the

AHI from 28 to 27 AH/h, even if proved significant with

larger samples, would not typify a therapeutic effect.

PSG variables, including measures of sleep architecture

and respiratory disturbance, were remarkably similar before

and after medication or placebo, as evidenced by the

reproducibility of the polysomnographic method. The effect

observed in the present study—a 32% reduction in the

amount of REM sleep in the SB group—denotes that

sibutramine shares this feature with the anti-depressants[13]

and attests, together with the increase in heart rate, that

sibutramine was actually administered.

The present results indicate that sibutramine does not

negatively affect sleep or breathing during sleep in men with

OSAHS.

Acknowledgements

Dr Martinez is employed by the UFRGS. Dr Basile was

recipient of a research scholarship from the Brazilian

National Research Council (CNPq). Abbott Laboratories

provided the medication and placebo and paid for the

second PSG. No personal advantages or contract of any kind

or of any amount were involved.

References

[1] Bonora M, St John WM, Bledsoe TA. Differential elevation by

protriptyline and depression by diazepam of upper airway respiratory

muscle activity. Am Rev Respir Dis 1985;131:41–5.

[2] Flemons WW. Obstructive sleep apnea. N Engl J Med 2002;347:

498–504.

[3] Berry RB, Kouchi K, Bower J, et al. Triazolam in patients with

obstructive sleep apnea. Am J Respir Crit Care Med 1995;151:450–4.

[4] Taansan V, Block A, Boysen P, et al. Alcohol increases sleep apnea and

oxygen desaturation in asymptomatic men. Am J Med 1981;71:240–5.

[5] Block A, Hellard D. Ingestion of either scotch or vodka induces equal

effects on sleep and breathing of asymptomatic subjects. Arch Intern

Med 1987;147:1145–7.

[6] Scanlan MF, Roebuck T, Little PJ, et al. Effect of moderate alcohol

upon obstructive sleep apnoea. Eur Respir J 2000;16:909–13.

[7] Yanovski SZ, Yanovski JA. Obes N Engl J Med 2002;346:

591–602.

[8] McNeely W, Goa KL. Sibutramine: a review of its contribution to the

management of obesity. Drugs 1998;56:1093–124.

[9] Young T, Evans L, Finn L, Palta M. Estimation of the clinically

diagnosed proportion of sleep apnea syndrome on middle-aged men

and women. Sleep 1997;20:705–6.

[10] Rechtschaffen A, Kales AA. A manual of standardized terminology,

techniques, and scoring system for sleep stages of human subjects.

Washington, DC: Public Health Service; 1968.

[11] Scholze J. Sibutramine in clinical practice —a PMS-study with

positive effects on blood pressure and metabolic parameters. Dtsch

Med Wochenschr 2002;127:606–10.

[12] Sharma AM. Sibutramine in overweight/obese hypertensive patients.

Int J Obes Relat Metab Disord 2001;25(Suppl 4):S20–S3.

[13] Rijnbeek B, de Visser SJ, Franson KL, et al. REM sleep effects as a

biomarker for the effects of antidepressants in healthy volunteers.

J Psychopharmacol 2003;17:196–203.