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Arthritic diseases such as rheumatoid
arthritis, osteoarthritis, ankylosing spondylitis and gout exhibit
profound circadian rhythms in the manifestation and intensity of
symptoms (1-4).
Rheumatoid Arthritis
Rheumatoid arthritis is a chronic
inflammatory autoimmune disorder. The cardinal signs of rheumatoid
arthritis are stiffness, swelling and pain of one or more joints of the
body characteristically most severe in the morning. Rheumatoid arthritis
shows a marked circadian variation in its symptoms. A group of British
volunteers self-assessed the pain and stiffness of affected finger
joints every 2 to 3 hours daily for several consecutive days. They also
measured the circumference of the arthritic joints to gauge the amount
of their swelling, and they performed grip strength tests to determine
the effect of the arthritic condition on the hands (1,2). Ratings of the
severity of joint pain swelling and stiffness were about 3 times higher
between 08:00 and 11:00 than at bedtime. In contrast, hand strength was
lower by as much as 30% in the morning than at night. This is typical of
rheumatoid arthritis sufferers (3-5).
Osteoarthritis
The circadian rhythm of pain and
stiffness in osteoarthritis differs from that of rheumatoid arthritis.
Osteoarthritis is a degenerative disease of the joints and is the
commonest of all joint diseases, affecting nearly everyone at least to
some degree by age 70. The weight bearing joints of the hip, knee, back,
toes and fingers are mostly affected.
The pain of osteoarthritis sufferers
is typically less intense in the morning than in the afternoon or
evening. This is illustrated by the findings of a Canadian study of 20
persons troubled with osteoarthritis of the knee (6). Participants did
pain self-ratings 10 times daily for 7 consecutive days. For the group
as a whole, pain intensity was rated about 40 percent higher on average
between 20:00 and midnight than between 06:00 and 10:00. However, the
exact nature of the 24-hour pattern of pain differed from person to
person. In 40 percent, pain was greatest between 14:00 and 20:00, and in
25 percent, it was highest between 20:00 and midnight. In 15 percent, it
peaked at 2 different times of the day, and in 20 percent, the level of
pain exhibited no day-night variation whatsoever. Interestingly, 40
percent of the people exhibited weekly rhythms in pain intensity,
although the exact day of the week it was worse varied. In some, it was
more intense at the end of the week and in others the beginning.
A French study on 57 osteoarthritis
sufferers also found great individual variation in the temporal patterns
in pain (7). In 33 percent, pain was most intense between 14:00 and
20:00. In 14 percent, it was worse between midnight and 08:00, and in 5
percent, it was worse between 08:00 and 14:00. A large proportion, 40
percent, had two peaks of pain daily, while 7 percent showed no temporal
pattern.
In summary, the day-night cycle of
pain in osteoarthritis varies from one individual to another. Some
experience worse pain in the morning and others at night. Some
experience 2 peaks, in the morning and evening, while still others
experience pain of equal intensity through out the 24 hours. The
successful treatment of osteoarthritis requires that medications be
taken at the right time relative to the day-night pattern of pain in
each person.
Ankylosing Spondylitis
Ankylosing spondylitis is
characterized by swelling and discomfort of the joints of the back. In
its occurrence it is an inherited disorder that is more common in men
than women. One investigator used questionnaires to study daily cycles
in the back symptoms of 39 people suffering from this disease (8).
Overall, back stiffness and pain were a problem throughout the 24 hours,
but pain intensity was rated 2 to 3 times higher and stiffness about 8
times greater between 06:00 and 09:00 than between noon and 15:00 when
each was least bothersome. The symptoms also exhibited a second less
prominent peak between 19:00 and 21:00. The findings of a French study
of 26 people suffering from this medical condition were identical (9).
Ratings of the intensity of back stiffness and pain were higher in the
morning and evening than in the afternoon. Marked seasonal variation in
ankylosing spondylitis was also prominent. The onset of backache and
stiffness was 12 times more frequent in winter than summer. Moreover,
reoccurrence of back problems occurs 2 to 3 times more often in winter
than summer (8).
Chronotherapy Arthritic Problems
The treatment of arthritic conditions
relies on medicines that fight joint swelling, stiffness, and pain.
Several European investigators have studied how rhythms affect arthritic
medications known as non-steroidal anti-inflammatory drugs, or NSAIDs
for short. NSAIDs reduce the swelling, stiffness, and pain of arthritis,
but they also cause disturbing side effects such as indigestion, stomach
ulcers, headache, anxiety and dizziness. The side effects of NSAIDs can
be so bothersome that some people must stop taking them.
A number of studies clearly show that
the time when NSAIDs and other anti-arthritic medicines are taken is
critical. Taking the medicines at the wrong time of day compromises
their effectiveness and increases the risk of side effects (10).
Chronotherapy provides ways of increasing the effectiveness and safety
of arthritis medications.
Chronotherapy of rheumatoid
Arthritis with NSAIDs
The chronotherapy of arthritic disease
involves determining the best time to take NSAIDs or other types of
medicines to enhance their desired effects and avoid or minimize
unwanted ones. Already in 1976, Huskisson discovered that an evening
once-a-day treatment schedule of the NSAID, indomethacin, was much more
effective in controlling the prominent morning symptoms of rheumatoid
arthritis than a morning one (5). Moreover, he found people much better
tolerated the medicine and with less complaint of side effects when
administered as a single daily dose in the evening than morning.
Another study examined the role of
treatment schedule on the therapeutic effect of the NSAID, flurbiprofen
(1). 17 rheumatoid sufferers self-assessed the severity of their
symptoms 6 times daily for 3 or 4 days while being treated by different
medication schedules. One schedule consisted of 4 small equal
flurbiprofen doses taken at equal intervals during the activity period.
Three other schedules consisted of 2 large doses that were taken at
different clock times during different weeks of study. For one week, the
medicine was taken in the morning and midday, for another in the morning
and at bedtime and for another at midday and bedtime. The twice-a-day
schedules, consisting of a large bedtime dose, best controlled the
bothersome morning symptoms of rheumatoid arthritis. The other treatment
schedules failed to control the morning symptoms. The findings of a
second study on flurbiprofen were exactly the same (11). To control the
morning symptoms of rheumatoid arthritis -- swelling, stiffness, and
pain, a large daily NSAID dose must be taken in the evening or at
bedtime.
Chronotherapy of Osteoarthritis with
NSAIDs
Medical interest in the chronotherapy
of osteoarthritis with NSAIDs commenced in Europe almost 20 years ago.
One French investigation evaluated the effect of a long-acting
ketoprofen product when taken at different times of day (12). On one
occasion 118 people took 200 milligrams of the medicine at 08:00 and a
look-alike inactive sugar-filled placebo pill at 20:00. On another, they
took the placebo in the morning and the active medicine at night. Both
treatment schedules were equally effective in controlling the symptoms
of osteoarthritis. However, taking the medicine in the morning rather
than evening caused twice as many people to experience bothersome side
effects, mainly stomach pain, nausea and diarrhea.
The largest study of the chronotherapy
of osteoarthritis with NSAIDs was conducted in France during the 1980s
(7). It involved 240 persons suffering from osteoarthritis of the hip,
240 suffering from osteoarthritis of the knee and 37 suffering from
osteoarthritis of some other joint. The object of the study was to
determine the best time to take the long-acting, once-a-day formulation
of indomethacin. Each participant did self-assessments of their pain
intensity every 2 hours during day and evening for a couple of days
before and after treatment. During different study weeks, people took
the medicine at a single time of day, either at 08:00, noon or 20:00.
The risk of experiencing bothersome side effects of the indomethacin was
strongly dependent on the time of day it was taken. Taking indomethacin
at 08:00 as opposed to 20:00 resulted in a quadrupling of the number of
complaints of dizzy spells, headaches, anxiety, nausea, stomach pain and
indigestion (7,13-16). Overall, 44 persons withdrew from the study
because of intolerable side effects of the medication. Remarkably, 66
percent of the withdrawals took place while taking indomethacin in the
morning.
The time of day the medicine produced
its best effect varied from person to person. The most fitting time to
take the medicine depended on the time of day pain was most intense.
Nearly 90 percent who experienced pain most intensely between 06:00 and
16:00 preferred a noon or evening treatment time. In contrast, 82
percent of those who experienced pain worse between 16:00 and 23:00
preferred a morning or afternoon treatment time (16). It was remarkable
how much the time of day of taking the medicine mattered. Taking the
once-a-day indomethacin medicine 4 to 8 hours before as opposed to after
the time of day pain was most intense in a patient resulting in a
doubling of its effectiveness!
Chronotherapy of Arthritis with
Corticosteroids
Severe forms of arthritis often
require treatment with corticosteroids such as prednisone, prednisolone,
methlyprednisolone and triamcinolone to control both pain and stiffness.
Unfortunately, when these are taken for a long period of time, they can
cause dangerous side effects, such as suppression of the endogenous
corticosteroids, stomach ulcers, bone weakening, cataract formation, and
mood alterations
The time of day these medicines are
taken determines the risk of suffering suppression of normal cortisone
production and other drug-induced side effects. Treatment schedules that
involve an evening or nighttime ingestion time result in greatest
cortisone suppression (17-19). Morning or early afternoon once-a-day
schedules are least detrimental (20). Thus, the best way to minimize or
avoid the side effects of these medications, especially when large doses
are involved, is to take them in the morning.
Morning is the safest time to take
cortisone-like medicines, but is this the right time to take them to
best control the symptoms of arthritic diseases? During the past 30
years, several research studies have assessed the safety and
effectiveness of various types of twice-a-day and once-a-day morning,
afternoon and evening treatment schedules for rheumatoid arthritis. Some
arthritis specialists recommend low dose cortisone-like medications at
bedtime over twice-a-day or morning once-a-day schedules, since they
feel it better controls the extreme pain and stiffness in the morning
(21,22). Others argue that taking even low doses of these medications at
bedtime can lead to harmful side effects (17-20,23). Three studies
compared the safety and efficiency of dosing schedules that involved
multiple daily doses to once-day morning ones (24-26). The results of
all the studies were the same. The 2 treatment schedules were equivalent
in controlling the prominent morning symptoms of rheumatoid arthritis;
however, morning dosing best avoided the development of drug-induced
side effects.
A group of British investigators
wondered if once-a-day treatment given at a time other than the morning
or evening would be more advantageous (27). Low dose prednisolone was
taken by a group of 12 rheumatoid arthritis sufferers during different
4-week study periods either at 08:00, 13:00, and 23:00. Hand grip
strength measurements and side effect assessments were done during the
last 3 days of each timed treatment. Side effects were uncommon no
matter the time of treatment. Inspection of the published grip strength
values shows that 60 to 70 percent of the rheumatoid arthritis sufferers
benefited to a greater extent from the 13:00 than the 08:00 treatment.
It is of interest that recent studies on asthma, a disease characterized
by swelling tissue of the air passages of the lung rather than the
joints as in arthritic conditions, shows a single daily 15:00 treatment
schedule of cortisone-like medications is better than a morning or
bedtime one.
Summary
1. The symptoms of rheumatoid
arthritis are always worse in the morning. Taking long-acting NSAIDs
like flubiprofen, ketoprofen and indomethacin at bedtime optimizes their
therapeutic effect and minimizes or averts their side effects. 12-hour
sustained-release NSAIDs that are taken twice a day must include a night
or bedtime ingestion time to ensure adequate control of the prominent
morning symptoms of rheumatoid arthritis.
2. The temporal pattern of pain and
stiffness in osteoarthritis sufferers differs between persons. Thus, an
individualized chronotherapy of NSAIDs is necessary. The chronotherapy
of osteoarthritis involves the administration of once-a-day forms of
ketoprofen, indomethacin and other such medicines in relation to the
time of day pain is worse. If pain is worse at night or early in
afternoon, an evening once-a day NSAID schedule is recommended. If pain
is worse in the afternoon or night, a once-a-day morning or noontime
treatment schedule is best, providing the amount of side effects
produced by the morning one, in particular, is minimal.
3. If the arthritic condition is
severe, synthetic corticosteroids are often of benefit. Morning
once-a-day dosing of these medicines is least likely to cause side
effects especially if they are taken for a long period of time.
Splitting the daily dose of medicine into several small ones for
ingestion with meals and at bedtime or taking the entire daily dose at
night is not recommended unless absolutely necessary. The risk of severe
side effects from these medications increases when they are taken more
than 8 to 9 hours after the customary time of awakening, after 15:00 for
most people. The later in the day these medications are taken, the
greater the risk of side effects. If the relief from the morning
symptoms of rheumatoid arthritis sufferers is not attained by a once-day
morning schedule, an increase in the morning dose is recommended. The
results of one study suggest an early afternoon once-a-day treatment
schedule might be beneficial for those people who fail to get
significant relief from the morning pain and stiffness of rheumatoid
arthritis when taking medicine in the morning.
*Summary of background information for chapter 15 in:
SMOLENSKY M.H. and LAMBERG.L : Body Clock Guide to Better Health ;
H.Holt , NY., 2001
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Chronobiology
and Chronotherapy of 