Response of Obstructive Sleep Apnea to Fluoxetine and Protriptyline* Douglas A. Hanzel, M.D.; Nicholas G. lroia, M.D.;t and
David W Hudgel, M.D., F.C.C.P.*
Protriptyline is the pbarmacologic agent most commonly used to treat obstructive sleep apnea (OSA); however, its anticbolinergic side effects make it intolerable to maily patients. Because serotonin may be a central respiratory stimulant and because the serotonin-uptake inhibitor, ftuoxetine, is usually well tolerated, we wanted to try ftuoxetine in the treatment of OSA. Therefore, we compared the effect of 8uoxetine to that o£ protriptyline in 11 patients with OSA. Both drugs significantly decreased the proportion of REM sleep time and decreased the number o£ apneas or hypopneas in NREM sleep. The response to ftuoxetine was equivalent to that of protriptyline; however,
reahnent of OSA other than by tracheostomy is T directed at maintaining upper airway patency during sleep. Since uvulopalatopharyngoplasty is reported to be effective in only approximately 50 percent of the cases 1-3 and since nasal CPAP may not be as effective on a long-term basis as over the short term,u pharmacologic treahnent of OSA would be ideal if.it were effective and safe. Protriptyline is commonly used to treat OSA. While reported to be effective in 50 to 70 percent of the cases of OSA, 7- 12 disturbing anticholinergic side effects limit its usefulness. Since some recent experiments report that serotonin may enhance central ventilatory activity1a-1e and since ventilatory stimulation may preferentially activate upper airway muscle activity relative to that of the diaphragm, 17- 19 we hypothesized that serotonin agonists would preferentially stimulate the activity of upper airway inspiratory muscles. This enhanced upper airway muscle activity would help preserve upper airway patency during sleep. 90 Consistent with our hypothesis is one report that shows that L-tryptophan, a serotonin precursor, has a bene&cial effect on OSA. 11 Therefore, we evaluated a speci&c serotonin agonist, fluoxetine, a serotonin re-uptake inhibitor, in the treatment of patients with OSA. To gauge its effectiveness, we compared the action of fluoxetine with that of protriptyline in the same patients. *From MetroHealth Medical Center, Cleveland. tAssistant Professor of Medicine, Northeast Ohio Univenity, Roots-
town.
~te
Professor of Medicine, Case Western Reserve Univenity,
Cleveland.
Supported by the Public Health Service and HL-42215 AG-04391. Manuscript niceived July 27; revision aa:epted November 6. Rsprint requeata: Dr. Htulgel, MetroHealth Medical Center; IWmonary, 3395 Scranton &ad, Cleoeland 44109
418
for the group as a whole, there was no signifieant improvement in the number of arterial oxygen desaturation events, the level of arterial oxygen desaturation, or the number of arousals with either agent. Although there was wide variability in the response to each medication, six of the 11 patients had good responses, including improvement in oxygenation, to either ftumetine or protriptyline. Three patients could not complete the trial of protriptyline. We conclude that ftum:etine is beneficial to some, but not all, patients with OSA. Flumetine was better tolerated than protriptyline. (Cheat 1991; 100:416-!l)
MATERIALS AND METHODS
Subjecta A prospective crossover unblinded trial was used to evaluate the ell'ect of fluoxetine and protriptyline in 12 patienb with OSA. All patienb were recruited from the Metroffealth Medical Center's Sleep Disorders Clinic. Criteria fur inclusion in the study were a history of heavy snoring, daytime hypersomnolence, and documented OSA by polysomnography. Patienb were considered for treatment if they had polysomnographic findings of recurrent obstructive apneas in NREM or REM sleep (or both) with apnearelated arterial oxygen desaturation below 85 percent saturation. Patienb were excluded if they had chronic rhinitis, parenchymal pulmoruiry diseases, any chronic cardiac, hemotologic, or endocrine diseases, alveolar hypoventilation manifested by daytime awake PaC01 greater than 50 mm Hg, cardiac arrhythmias requiring treatment, or facial anatomic abnormalities. Patienb who carried a psychiatric diagnosis were not studied. No one was studied who had a contraindication to taking protriptyline, such as glaucoma or prostatic hypertrophy. Patienb with tonsillar hypertrophy or an obviously narrowed pharynx observed on physical examination were not excluded from the study. All patienb who met these criteria fur inclusion and who chose pbarmaoologic treatment fur OSA from August 1987 to December 1989 were informed about this protocol and included ifthey volunteered. 76chnfqflea Polysomnograms were perfurmed in the sleep laboratory between approximately 10 PM and 7 AM. Sleep stages were monitored by standard techniques.• Airflowwas measured at the nose and mouth with thermistors. Oxygen saturation was recorded with a finger pulse oximeter (Nellcor). Precordial electrocardiographic leads recorded heart rate and rhythm. Chest wall muscle electrical respiratory activity was recorded by surface electrodes placed at the right costal margin in the seventh and eighth inten:ostal spaces in the anterior axillary line.11 A polygraph (Grass Instrumenb model 7) ran continuously at 10 mm/s to record all physiologic data throughout the night.
Protocol After a baseline polysomnogram documented OSA, patienb who Fluoxellne and PIUlllptyllna In OSA {Hanzel, Proia. Hudge/}
Table 1-Morphmnetric:. ofl!tdienla antl Skep Stage Didribution* Patient,
Sex,
Wtlght,
Age(yr)t
kg
l,F,61 2,F,65 3,M,41 4,F,sei 5,F,~
6,M,47 7,M,4l:j: 8,M,53 9,M,42 10,M,59 11,F,60 12,M,58 Mean±SE
NREMSleep, percent of sleep
Sleep Latency, min
93 66
105 70 120.5 159 100
96 91
f11 83 102 99±7
REM Sleep, percent of sleep
Height, cm
B
F
p
B
F
p
B
F
p
168 157 188 160 165 180 180 178 180 170 168 188 174±3
2 12.5 2.0 7.0 3.5 3.5 12.5 1.0 0 4.5 0 1.0 4.1±1.l
8 27.0 2.0 47.0 5.5 1.0 10.5 2.0 0 7.0 12.5 2.0 10.9±4.2
6 18.0 5.5
86
100 100
96 96 99
14 14 7 23 10 15 24 12 21 16 26 19 17±2
0 0 4 2 10 4 10 55 75 39 0 3 7±3
3 2 l
2.0 0.5 4 32.5 0 2.0 7.8±3.6
86 93 93 76§ 90
84 76 88 70
98 90
96 75
92
95 95
98 98 100 100 ffT±l
93
84
48
74 81 82±2
100
f11 91±4
7
2 0 0 3±1
*B, Baseline study; F, fluoxetine trial; and P, protriptyline trial. tMeanage, 51±3yr. *No protriptyline in these individuals (same on subsequent tables). §When sum of percents of sleep in REM and stages 1 and 2 do not add up to 100 percent, stages 3 and 4 or unscorable epochs make up remaining percent.
agreed to participate in this protocol were placed on therapy with either fluoxetine (20 mg/day) or protriptyline (10 mg/day). Alternate patients were started on fluoxetine first. Patients were told of possible side eft'ects of each medication. After four weeks of treatment, a repeat polysomnogram was performed. A one-week washout period IOllowed, and patients were started on the alternate medication. Again after four weeks of treatment, polysomnography was performed.
DataAnalym The following guidelines were used to evaluate the polysomnograms. Apneas were de6ned as cessation of airflow at the nose and mouth IOr 10 s or longer. An apnea was considered obstructive when
chest wall phasic inspiratory electrical activity continued during the period of absent airflO\\t A hypopnea was de&ned as at least a 50 percent reduction in inspiratory airflow from the pre-apnea level lasting more than 10 s. A desaturation event was recorded when the arterial oxygen saturation dropped by at least 4 percent from the level before the event. An arousal was recorded if there was an awake EEG pattern and an increase in submental EMC activity of at least 3 s in duration. Sleep records were scored by a sleep laboratory technician who was not aware of the anticipated pharmacologic response. Records were not blinded as to whether they were baseline or therapeutic studies. Analysis of variance was used to compare baseline values before the drugs with those obtained while talcing fluoxetine and protriptyline. A Pearson correlation coefficient was used to evaluate the association between both body weight and age and the response to each drug. An unpaired t-test was used to compare body weight and age between the better and poorer responders to each agent. Significance level was p:S0.05. RESULTS
Subject Chara.cteristics Seven men and five women were studied (Table 1). Six men and three women completed both ftuoxetine and protriptyline trials. An additional man and two women completed the ftuoxetine trial. The male patient was unable to complete the protriptyline trial because of severe dysuria. One female patient could
not continue taking protriptyline because of intolerable "nervousness." The other woman had to be withdrawn from the study because of the occurrence of an unrelated illness. No patient had intolerable side effects from ftuoxetine. Ages ranged from 25 to 65 years, withameanof51±3years (±SE). Bodyweight ranged from 66 to 159 kg, with a mean of 99 ± 7 kg.
Sleep Stage Distribution Both protriptyline and ftuoxetine altered sleep architecture, with a significant reduction in REM sleep from a baseline predrug rate of 17 ± 2 percent of total sleep time to 3 ± 1 percent with protriptyline and 7 ± 3 percent with ftuoxetine, respectively (F = 8.38; p
David W Hudgel, M.D., F.C.C.P.*
Protriptyline is the pbarmacologic agent most commonly used to treat obstructive sleep apnea (OSA); however, its anticbolinergic side effects make it intolerable to maily patients. Because serotonin may be a central respiratory stimulant and because the serotonin-uptake inhibitor, ftuoxetine, is usually well tolerated, we wanted to try ftuoxetine in the treatment of OSA. Therefore, we compared the effect of 8uoxetine to that o£ protriptyline in 11 patients with OSA. Both drugs significantly decreased the proportion of REM sleep time and decreased the number o£ apneas or hypopneas in NREM sleep. The response to ftuoxetine was equivalent to that of protriptyline; however,
reahnent of OSA other than by tracheostomy is T directed at maintaining upper airway patency during sleep. Since uvulopalatopharyngoplasty is reported to be effective in only approximately 50 percent of the cases 1-3 and since nasal CPAP may not be as effective on a long-term basis as over the short term,u pharmacologic treahnent of OSA would be ideal if.it were effective and safe. Protriptyline is commonly used to treat OSA. While reported to be effective in 50 to 70 percent of the cases of OSA, 7- 12 disturbing anticholinergic side effects limit its usefulness. Since some recent experiments report that serotonin may enhance central ventilatory activity1a-1e and since ventilatory stimulation may preferentially activate upper airway muscle activity relative to that of the diaphragm, 17- 19 we hypothesized that serotonin agonists would preferentially stimulate the activity of upper airway inspiratory muscles. This enhanced upper airway muscle activity would help preserve upper airway patency during sleep. 90 Consistent with our hypothesis is one report that shows that L-tryptophan, a serotonin precursor, has a bene&cial effect on OSA. 11 Therefore, we evaluated a speci&c serotonin agonist, fluoxetine, a serotonin re-uptake inhibitor, in the treatment of patients with OSA. To gauge its effectiveness, we compared the action of fluoxetine with that of protriptyline in the same patients. *From MetroHealth Medical Center, Cleveland. tAssistant Professor of Medicine, Northeast Ohio Univenity, Roots-
town.
~te
Professor of Medicine, Case Western Reserve Univenity,
Cleveland.
Supported by the Public Health Service and HL-42215 AG-04391. Manuscript niceived July 27; revision aa:epted November 6. Rsprint requeata: Dr. Htulgel, MetroHealth Medical Center; IWmonary, 3395 Scranton &ad, Cleoeland 44109
418
for the group as a whole, there was no signifieant improvement in the number of arterial oxygen desaturation events, the level of arterial oxygen desaturation, or the number of arousals with either agent. Although there was wide variability in the response to each medication, six of the 11 patients had good responses, including improvement in oxygenation, to either ftumetine or protriptyline. Three patients could not complete the trial of protriptyline. We conclude that ftum:etine is beneficial to some, but not all, patients with OSA. Flumetine was better tolerated than protriptyline. (Cheat 1991; 100:416-!l)
MATERIALS AND METHODS
Subjecta A prospective crossover unblinded trial was used to evaluate the ell'ect of fluoxetine and protriptyline in 12 patienb with OSA. All patienb were recruited from the Metroffealth Medical Center's Sleep Disorders Clinic. Criteria fur inclusion in the study were a history of heavy snoring, daytime hypersomnolence, and documented OSA by polysomnography. Patienb were considered for treatment if they had polysomnographic findings of recurrent obstructive apneas in NREM or REM sleep (or both) with apnearelated arterial oxygen desaturation below 85 percent saturation. Patienb were excluded if they had chronic rhinitis, parenchymal pulmoruiry diseases, any chronic cardiac, hemotologic, or endocrine diseases, alveolar hypoventilation manifested by daytime awake PaC01 greater than 50 mm Hg, cardiac arrhythmias requiring treatment, or facial anatomic abnormalities. Patienb who carried a psychiatric diagnosis were not studied. No one was studied who had a contraindication to taking protriptyline, such as glaucoma or prostatic hypertrophy. Patienb with tonsillar hypertrophy or an obviously narrowed pharynx observed on physical examination were not excluded from the study. All patienb who met these criteria fur inclusion and who chose pbarmaoologic treatment fur OSA from August 1987 to December 1989 were informed about this protocol and included ifthey volunteered. 76chnfqflea Polysomnograms were perfurmed in the sleep laboratory between approximately 10 PM and 7 AM. Sleep stages were monitored by standard techniques.• Airflowwas measured at the nose and mouth with thermistors. Oxygen saturation was recorded with a finger pulse oximeter (Nellcor). Precordial electrocardiographic leads recorded heart rate and rhythm. Chest wall muscle electrical respiratory activity was recorded by surface electrodes placed at the right costal margin in the seventh and eighth inten:ostal spaces in the anterior axillary line.11 A polygraph (Grass Instrumenb model 7) ran continuously at 10 mm/s to record all physiologic data throughout the night.
Protocol After a baseline polysomnogram documented OSA, patienb who Fluoxellne and PIUlllptyllna In OSA {Hanzel, Proia. Hudge/}
Table 1-Morphmnetric:. ofl!tdienla antl Skep Stage Didribution* Patient,
Sex,
Wtlght,
Age(yr)t
kg
l,F,61 2,F,65 3,M,41 4,F,sei 5,F,~
6,M,47 7,M,4l:j: 8,M,53 9,M,42 10,M,59 11,F,60 12,M,58 Mean±SE
NREMSleep, percent of sleep
Sleep Latency, min
93 66
105 70 120.5 159 100
96 91
f11 83 102 99±7
REM Sleep, percent of sleep
Height, cm
B
F
p
B
F
p
B
F
p
168 157 188 160 165 180 180 178 180 170 168 188 174±3
2 12.5 2.0 7.0 3.5 3.5 12.5 1.0 0 4.5 0 1.0 4.1±1.l
8 27.0 2.0 47.0 5.5 1.0 10.5 2.0 0 7.0 12.5 2.0 10.9±4.2
6 18.0 5.5
86
100 100
96 96 99
14 14 7 23 10 15 24 12 21 16 26 19 17±2
0 0 4 2 10 4 10 55 75 39 0 3 7±3
3 2 l
2.0 0.5 4 32.5 0 2.0 7.8±3.6
86 93 93 76§ 90
84 76 88 70
98 90
96 75
92
95 95
98 98 100 100 ffT±l
93
84
48
74 81 82±2
100
f11 91±4
7
2 0 0 3±1
*B, Baseline study; F, fluoxetine trial; and P, protriptyline trial. tMeanage, 51±3yr. *No protriptyline in these individuals (same on subsequent tables). §When sum of percents of sleep in REM and stages 1 and 2 do not add up to 100 percent, stages 3 and 4 or unscorable epochs make up remaining percent.
agreed to participate in this protocol were placed on therapy with either fluoxetine (20 mg/day) or protriptyline (10 mg/day). Alternate patients were started on fluoxetine first. Patients were told of possible side eft'ects of each medication. After four weeks of treatment, a repeat polysomnogram was performed. A one-week washout period IOllowed, and patients were started on the alternate medication. Again after four weeks of treatment, polysomnography was performed.
DataAnalym The following guidelines were used to evaluate the polysomnograms. Apneas were de6ned as cessation of airflow at the nose and mouth IOr 10 s or longer. An apnea was considered obstructive when
chest wall phasic inspiratory electrical activity continued during the period of absent airflO\\t A hypopnea was de&ned as at least a 50 percent reduction in inspiratory airflow from the pre-apnea level lasting more than 10 s. A desaturation event was recorded when the arterial oxygen saturation dropped by at least 4 percent from the level before the event. An arousal was recorded if there was an awake EEG pattern and an increase in submental EMC activity of at least 3 s in duration. Sleep records were scored by a sleep laboratory technician who was not aware of the anticipated pharmacologic response. Records were not blinded as to whether they were baseline or therapeutic studies. Analysis of variance was used to compare baseline values before the drugs with those obtained while talcing fluoxetine and protriptyline. A Pearson correlation coefficient was used to evaluate the association between both body weight and age and the response to each drug. An unpaired t-test was used to compare body weight and age between the better and poorer responders to each agent. Significance level was p:S0.05. RESULTS
Subject Chara.cteristics Seven men and five women were studied (Table 1). Six men and three women completed both ftuoxetine and protriptyline trials. An additional man and two women completed the ftuoxetine trial. The male patient was unable to complete the protriptyline trial because of severe dysuria. One female patient could
not continue taking protriptyline because of intolerable "nervousness." The other woman had to be withdrawn from the study because of the occurrence of an unrelated illness. No patient had intolerable side effects from ftuoxetine. Ages ranged from 25 to 65 years, withameanof51±3years (±SE). Bodyweight ranged from 66 to 159 kg, with a mean of 99 ± 7 kg.
Sleep Stage Distribution Both protriptyline and ftuoxetine altered sleep architecture, with a significant reduction in REM sleep from a baseline predrug rate of 17 ± 2 percent of total sleep time to 3 ± 1 percent with protriptyline and 7 ± 3 percent with ftuoxetine, respectively (F = 8.38; p
