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Nonsteroidal antiinflammatory drug therapy in rheumatoid arthritis patients. Lack of association between clinical improvement and effects on sleep

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655
NONSTEROIDAL ANTIINFLAMMATORY DRUG
THERAPY IN RHEUMATOID ARTHRITIS PATIENTS
Lack of Association Between Clinical Improvement and Effects on Sleep
P. LAVIE, M . NAHIR, M . LORBER. and Y. SCHARF
Thirteen patients with rheumatoid arthritis
(mean & SD age 55.8 f 10.5 years) received 20 mg of
tenoxicam daily for 90 days following a 3-7-day “washout” period and 4 days of placebo treatment. Clinical
evaluations were conducted at the end of the washout
period and at monthly intervals thereafter. All-night
polysomnography was performed in a sleep laboratory
during the last 2 days of placebo treatment and on days
13, 14, 89, and 90 of tenoxicam treatment. Although
there was improvement in the patients’ clinical condition, there were no treatment-related changes in any of
the sleep parameters. Eight of the 13 patients, however,
were found to have primary sleep disorders. Four had
periodic leg movements during sleep, 3 had sleep apneas, and 1 had a combination of both disorders. The
implications of these findings in the treatment of sleep
disorders in patients with rheumatoid arthritis are
discussed.
The association of chronic arthritic pain with
subjective complaints of sleep disturbances and sleep
abnormalities is well documented (1-4). These include
disturbances in the continuity of sleep, as well as in the
qualitative aspects of electroencephalographic (EEG)
-
From the Sleep Laboratory, Faculty of Medicine, Technion, and the Department of Rheumatology, Rambam Medical
Center, Haifa, Israel.
Supported in part by Hoffman-La Roche, Basel, Switzerland.
P. Lavie, PhD: Technion; M. Nahir, MD: Rambam Medical
Center; M. Lorber, MD: Rambam Medical Center; Y. Scharf, MD:
Rambam Medical Center.
Address reprint requests to P. Lavie, PhD, Sleep Laboratory. Faculty of Medicine, Gutwirth Building.
- Technion. Haifa
32000, Israel:
Submitted for publication May 24, 1990; accepted in revised
form December 31, 1990.
Arthritis and Rheumatism, Vol. 34, No. 6 (June 1991)
activity during sleep (5,6). It has been reported that,
aside from nonspecific pain-related disturbances of
sleep, patients with rheumatoid arthritis (RA) may also
have primary sleep disorders. Periodic leg movements
during sleep and the restless legs syndrome (7), as well
as breathing disorders during sleep (7,8), have been
observed in RA patients. Thus, questions concerning
treatment approaches for the sleep-disturbed RA patient arise: Should therapy concentrate primarily on
relieving pain and stiffness (9), or should treatment be
aimed at the patient’s specific sleep disorder?
In the present study, we evaluated the efficacy
of treatment with a nonsteroidal antiinflammatory drug
(NSAID), tenoxicam, according to clinical and sleep
parameters in patients with RA.
PATIENTS AND METHODS
Patient population. Fifteen consecutive female outpatients at the Department of Rheumatology, Rambam Medical Center, were asked to participate in the study. They
were compensated for their participation with an expensespaid weekend at a resort hotel. Thirteen women (mean age
55.8 2 10.5 years) agreed to participate. Two had declined
because of difficulty with getting to the sleep laboratory.
All patients had been diagnosed as having active
classic or definite RA, according to the American Rheumatism Association criteria (10). The mean (?SD) disease
duration was 95.6 2 53.6 months. Concomitant diseases
were hypertension (2 patients), hypertension plus hyperlipidemia, hypertension plus asthma, thalassemia minor, nephrolithiasis, anemia, and angina pectoris (1 patient each).
None of the patients was obese, and none was a habitual
cigarette smoker. None had a history of peripheral neuropathy.
Study design. After agreeing to participate in the
study and signing an informed consent form, patients began
a 3-7-day “washout” period during which all NSAIDs were
LAVIE ET A L
656
Table 1. Changes in clinical parameters of disease activity in 13 rheumatoid arthritis patients treated with tenoxicain*
Morning stiffness (minutes)
Pain
During the morning (0-120-mm VAS)
During the day (0-120-mm VAS)
During sleep (0-4scale)
With movement (0-4 scale)
Ritchie articular index
Number of swollen joints
Grip strength, left plus right (mm Hg)
Day 0
Day 30
Day 60
89.6 2 18.9
48.1 2 11.5
41.2 2 12.3
42.1 t 13.2
90.1 f 6.1
54.6 2 4.5
1.46 t 0.24
2.23 t 0.12
10.2 2 1.3
3.8 2 0.7
122.8 ? 11.3
65.8 f 10.9
42.9 t 4.9
0.77 f 0.23
1.61 f 0.26
9.0 2 1.4
2.8 2 0.8
134.4 f 13.7
51.8 2 10.1
33.7 2 5.7
0.57 2 0.17
1.3 f 0.21
6.5 t 1.2
2.0 2 0.7
140.0 2 18.8
47.7 t 10.1
37.9 t 8.1
0.91 f 0.26
1.10 f 0.26
6.6 t 1.4
1.6 t 0.8
137.08 ? 18.3
Day 90
P
0.06
0.01
0.08
0.05
0.003
0. I4
0.06
NS
* Values are the mean f SD. See Patients and Methods for explanation of scoring systems used. Day 0 = the last day of the “washout” period.
VAS = visual analog scale; NS = not significant.
discontinued. This was followed by a 4-day placebotreatment period, which was immediately followed by a
3-month period of daily tenoxicam treatment. Tenoxicam (20
mg) was taken once each day, during the morning. Treatment with second-line medications (hydroxychloroquine in 1
patient, aurothiomalate in 3 patients, sulfasalazine in 5
patients, and methotrexate in 2 patients) and with prednisone (2 patients, 5 mg/day) was continued throughout the
study. Patients were permitted to use paracetamol if additional analgesia was required.
Clinical assessment. Clinical assessments were conducted at the end of the “washout” period and at monthly
intervals thereafter. The following parameters were evaluated: duration of morning stiffness (in minutes), number of
tender and swollen joints, pain (by 0-120-mm visual analog
scale) in the morning, daytime, and evening, pain during
sleep (4 categories: not at all, a little, moderate, and severe),
pain associated with movement (4 categories), Ritchie articular index (number of affected joints, either tender or swollen), and grip strength (in mm Hg; mean of values for right
and left hands, each measured 3 times).
Polysomnography. All-night polysomnographic recordings were made of all patients on the last 2 days of
placebo therapy and on days 13, 14,89, and 90 of tenoxicam
treatment. These included an EEG, electrooculogram, submental electromyogram, and electrocardiogram, as well as
recordings of leg movements (by accelerometer, attached to
the back of the foot) and wrist movements (by actigraphy).
Respiration (by nostril thermistors and respiratory belt) was
recorded during the last 2 assessments only. Each patient
had a private bedroom, w h i c h w a s d a r k e n e d , a i r conditioned, and sound-attenuated.
Sleep records were scored according to standard
criteria (1 l), for stage 1, non-rapid eye movement (nonREM) sleep stages 2, 3, and 4 (deepest level), REM sleep,
and wake-within-sleep. Non-REM stages 2 , 3, and 4 were
combined into a single non-REM category because most
patients had excessive alpha activity, which made it difficult
to differentiate between these stages. All sleep records were
scored by the same scorer, who had no knowledge of the
treatment phase during which the tracing had been made
(before or after treatment).
Episodes of sleep apneas and periodic leg movements were also scored. Central apnea was defined as a
cessation of respiratory effort for at least 10 seconds, ob-
structive apnea was cessation of oral-nasal airflow, despite
persisting respiratory effort, for at least 10 seconds, and
mixed apnea was apnea beginning as a central type and
changing to an obstructive form. Leg movements were
scored according to the method of Coleman et a1 (12). The
results of wrist actigraphy are not presented in this report.
RESULTS
Clinical findings. Comparison of the clinical parameters on day 0 (last day of washout period) with those
on treatment days 30,60, and 90 revealed an improvement in all clinical parameters (Table 1). Improvement
in most parameters was evident on day 30, remaining
stable or improving further by the end of the study.
Except for the Ritchie articular index and grip strength
values, the effects of treatment were statistically significant or bordered on statistical significance, as assessed by repeated-measurements analysis of variance. None of the patients reported side effects that
necessitated changing the experimental protocol.
Sleep parameters. Data for 12 of the 13 patients
were included in the analyses of the polysomnographic
studies. One patient failed to fall asleep on 3 of the 6
assessment nights, and those data were not included.
Comparison of the sleep data of t h e first and second
night of each of the 3 pairs of nights tested indicated
more efficient sleep during the second nights, which is
suggestive of a “first night effect” (13). Because the
sleep parameters of the first nights and second nights
of each pair were highly positively correlated, we used
the mean of each pair for the statistical analyses
(Table 2).
Generally, across all nights tested, these patients had severely fragmented sleep. This was manifested in high percentages of wake plus movement
time within sleep, reduced percentages of REM sleep,
and low sleep efficiency indices (ratio of total sleep
NSAID EFFECTS ON CLINICAL AND SLEEP PARAMETERS IN RA
Table 2. Changes in parameters of sleep in 12 rheumatoid arthritis
patients treated with tenoxicam*
Placebo
Total bed time
(minutes)
Total sleep time
(minutes)
Sleep latency
(minutes)
REM latency
(minutes)
Sleep efficiency (%)
Number of
awakenings
Time in sleep stages
Tenoxicam I
352.1
f
35.4
356.5
f
54.3
338.7 t 34.7
319.9
f
41.8
274.8
f
50.7
21.8 t 15.5
27.1
2
23.1
19.8 t 119.5
91.2 t 31.5
93.0 t 35.5
80.0 :t 23.7
76.2 t 10.1
13.9 2 3.4
77.4 t 12.5
11.6 t 6.5
77.3 f ’77.3
14.3 :k 4.5
(%)
Wake-within-sleep
Movement-withinsleep
Stage 1
Stages 2, 3, and 4
non-REM sleep
REM sleep
Table 3. Number of episodes of periodic leg movements during
sleep in 12 rheumatoid arthritis patients treated with tenoxicam*
Tenoxicarn I1
361.9 t 32.2
18.4 t 11.1
4.4 t 3.0
18.3 t 12.9
2.9 t 1.5
19.1 f 12.5
2.7 t 1.9
0.9 t 0.9
61.9 t 8.2
0.5 t 0.2
64.3 t 9.2
0.7
62.0
?
f
0.4
7.5
14.4 2 3.5
14.5 t 6.4
15.3
?
6.0
* Patients were evaluated by polysomnographic studies on the last 2
days of a 4-day placebo-treatment period. on days 13 and 14 of
tenoxicam treatment (tenoxicam I), and on days 89 and 90 of
tenoxicam treatment (tenoxicam 11). Values are the mean f SD for
these “pairs” of nights. One patient could not sleep on 3 of the 6
nights evaluated, and those data were not included here. See
Patients and Methods for explanations of categories assessed. REM
= rapid eye movement.
time to total bed time). There were no significant
differences between the mean of the first pair of
recordings taken during placebo therapy and the
means of the 2 pairs of recordings taken during tenoxicam treatment for any of the sleep parameters tested.
The mean sleep efficiency indices for the 3 pairs of
recordings were essentially the same (76%, 77%, and
77%).
Primary sleep disorders identified. Five patients
had a mean of more than 40 episodes of periodic leg
movements during sleep (Table 3), which is considered
clinically significant. Their mean number of periodic
leg movements for the 6 nights studied ranged from
60.5 to 157.5. There was remarkable night-to-night
variation in the number of episodes. Some of the
patients who had fewer than 40 episodes of periodic
leg movements per night had a large number of such
episodes during some of the nights. Patient 4 had 90
episodes on the first night assessed, and patient 12 had
120 episodes when assessed on treatment night 13.
Four patients had a significant number of episodes of sleep apnea on treatment nights 89 and 90
(Table 4). Patient 2, who had 201 and 212 episodes of
apnea, respectively, could not fall asleep on 3 of the 6
657
Tenoxicam
1
Tenoxicam
11
2
13
14
89
90
Mean
0
37
0
22
0
0
NA
72
93
0
120
43
29
120
47
26
0
8
41
26
NA
0
40
0
106
161
30
60
NA
16
15
136
8
NA
0
0
19
35
64
8
44
NA
21
7
111
10.0
17.0
29.6
120.0
157.5
13.0
97.3
63.0
18.8
33.0
60.5
Placebo
Patient
1
2t
3
4
5
6
7
8t
9
10t
II
12t
13
1
0
0
90
0
NA
190
10
170
NA
10
15
69
0
8
287
280
10
125
133
8
4
0
100
157
20
65
13
29
37
0
* Patients were evaluated by polysomnographic studies as described
in Table 2. Patient 2 could not sleep on 3 of the 6 nights evaluated
(nights I , 2, and 14). NA = not assessed.
i- These patients had sleep apneas (see Table 4).
nights tested. Patient 10, who had 190 and 266 apneic
episodes, also had a mean of more than 40 episodes of
periodic leg movements. Two other patients (patients
8 and 12) had a considerable number of episodes of
apnea, particularly during REM sleep. Most of the
apneas were of the obstructive and mixed types.
A total of 8 of the 13 RA patients (61.5%)
exhibited a primary sleep disorder, either periodic leg
movements or sleep apneas, or both. Patients with
sleep apnea were significantly older than those with
periodic leg movements, as well as those without a
primary sleep disorder (mean t- SD age 66 k 4.9,46 2
3.7, and 56 2 3.8, respectively; F = 5.0, P < 0.03).
Table 4. Number of episodes of sleep apnea in 4 rheumatoid
arthritis patients treated with tenoxicam*
~~~~~
Tenoxicam day 89
Patient
2
8
10
12
~~~~~
Tenoxicam day 90
Total
Apnea
index
Total
Apnea
index
20 I
50
190
64
34.9
9.3
41.2
10.4
212
40
266
140
45.5
7.9
74.1
23.3
* Of the 13 patients evaluated by polysomnographic studies (see
Table 2 and Patients and Methods for details), these 4 had a
significant number of episodes of sleep apnea at the end of the
90-day course of tenoxicam therapy. The apnea index was calculated by dividing the total number of apnea episodes by the total
number of hours of sleep.
LAVIE ET AL
658
Response to treatment as a function of sleep
disorder type. Analysis of the clinical response to
tenoxicam as a function of the type of sleep disorder
revealed that the 4 patients with sleep apnea had the
smallest improvement in all clinical parameters between day 0 and day 90. The 5 patients with no
primary sleep disorder had the largest improvement.
For example, while in patients free of primary sleep
disorders, the duration of morning stiffness was reduced by 77 minutes, 83 minutes, and 76 minutes after
30 days, 60 days, and 90 days of tenoxicam treatment,
respectively, none of these reductions was greater
than 25 minutes in patients with sleep apnea or in
patients with periodic leg movements. Furthermore, in
3 of the 4 patients with sleep apnea, the global effect of
tenoxicam therapy was inadequate, as evaluated by
the physician. Because of the small number of patients
in each group, these differences were not statistically
significant.
DISCUSSION
The present study shows that despite a significant improvement in the RA patients’ clinical condition after treatment with tenoxicam, there was no
comparable improvement in sleep parameters. Thus,
although by the end of the treatment period, patients
reported significantly less pain during sleep and
shorter duration of morning stiffness, they nevertheless experienced fragmented sleep. These findings are
consistent with our previously reported findings of the
effects of NSAID treatment on sleep in a different
group of RA patients (14). In that double-blind, parallelgroups study, we investigated the effects of 2 NSAIDs,
tenoxicam and diclofenac, versus placebo on clinical
and sleep parameters in RA patients. Sleep was investigated by actigraphy, which differentiated between
sleep and waking by level of spontaneous movement.
We found that, despite a significant improvement in
the clinical conditions of both drug-treatment groups
compared with the placebo-treated group, there were
no drug-related effects on any of the actigraphically
derived sleep parameters. Recently, Leigh et a1 (15)
reported that tenoxicam (20 mg/day) produced no
significant changes in either objective or subjective
parameters of sleep in patients with osteoarthritis.
But, in that study, tenoxicam also did not produce any
significant changes in the level of pain or the number of
early morning awakenings.
The lack of effect of NSAID treatment on
parameters of sleep is not surprising, however, con-
sidering the fact that 8 of the 13 patients had a primary
sleep disorder. Four patients had a considerable number of episodes of sleep apnea and 4 patients had
periodic leg movements in sleep, 1 of whom also had
sleep apnea. These findings are consistent with those
in the recent report by Mahowald et al (7), who
obtained polysomnographic recordings for 1 night
from 16 RA patients. Those authors reported that all
16 RA patients had frequent movements of the extremities and frequent arousals. In 2 patients, they also
found unanticipated sleep apnea. Thus, the present
findings, and the previous reports on increased rates of
periodic leg movements during sleep in RA patients,
indicate that RA patients are at risk for developing
disordered motor activity in sleep.
Since periodic leg movement has been reported
to be preponderant among individuals 60-79 years of
age (16), it could be argued that the high rate found in
RA patients is not specific to RA. This explanation
seems unlikely, however, since we found that patients
who had such episodes were younger than the patients
with sleep apnea as well as the patients without a
primary sleep disorder. We have no immediate explanation for the high risk for this disorder in RA.
Episodes of periodic leg movements are also preponderant among patients who require dialysis (17), patients with diabetes (IS), and patients with the fibrositis syndrome (19). Peripheral neuropathies may,
perhaps, play some etiologic role.
We also cannot explain the high rate of sleep
apnea in RA patients. Given the extremely low rate of
sleep apnea among women, it is very unlikely that the
findings of our study are a chance event. Although
sleep apnea has been documented in some individual
cases of RA, it was associated with anatomic changes
known to increase the risk for sleep apnea (8). As in
Mahowald and coworkers’ study, our finding of sleep
apnea was unanticipated. When interviewed prior to
the study, none of our study patients was suspected of
having breathing disorders during sleep. The fact that
the 4 patients who had sleep apnea were significantly
older than the rest of the patients studied may suggest
a contributing role of aging. Certainly, further studies
are needed in order to determine whether our findings
reflect the true incidence of sleep apnea in RA.
The lack of association between the clinical
effects of tenoxicam and its effects on sleep parameters clearly indicates that decisions regarding treatment of sleep-disturbed RA patients should be made
individually, after a proper evaluation. Periodic movement in sleep has been shown to be effectively treated
NSAID EFFECTS ON CLINICAL AND SLEEP PARAMETERS IN RA
with low doses of clonazepam (20). Treatment of a
sleep apnea syndrome should b e evaluated in light of
t h e severity a n d t y p e of apnea a n d t h e coexistence of
excess b o d y weight and/or upper airways abnormalities. Since hypnotic drugs are commonly prescribed
for rheumatic disease patients, physicians should b e
aware of t h e possible presence of a unanticipated sleep
a p n e a syndrome, which could b e worsened by such
hypnotic drugs. T h e fact that patients with sleep a p n e a
tended to s h o w less response to tenoxicam suggests
that disturbed breathing in sleep may aggravate a
patient’s clinical condition.
Finally, the findings of t h e present study also
raise some q u e s t i o n s regarding the relevance of
changes in sleep behavior, as subjectively reported by
t h e RA patient, to the efficacy of t h e NSAID. T h e lack
of association between the clinical efficacy of tenoxicam a n d its effects on sleep suggests that reported
changes in sleep after treatment with NSAIDs should
b e interpreted with great caution.
ACKNOWLEDGMENTS
The excellent technical assistance of V. Ian-co, 0.
Tzischinsky, R. Epstein, and S. Medan is greatly appreciated.
8.
9.
10.
11.
12.
13.
14.
15.
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