European Journal of Internal Medicine 24 (2013) 698–706

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Review article

Circadian rhythms and medical diseases: Does it matter when drugs

are taken?
Alfredo De Giorgi a, Alessandra Mallozzi Menegatti a, Fabio Fabbian a,
Francesco Portaluppi b, Roberto Manfredini a,⁎
a
Clinica Medica, Azienda Ospedaliera-Universitaria, Ferrara, Italy
b
Hypertension Unit, Clinica Medica, Azienda Ospedaliera-Universitaria, Ferrara, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Background: Chronobiology is devoted to the study of biological rhythms. It is possible that a given medica-
Received 14 February 2013 tion may be therapeutic and safe when administered at some time, but subtherapeutic or poorly tolerated at
Received in revised form 19 March 2013 another.
Accepted 26 March 2013 Methods: We focused on some classes of drugs, widely used by the internists, performing a PubMed search with
Available online 21 April 2013
the single drugs associated with the MeSH terms “Chronotherapy”, “Circadian rhythm”, and “Chronobiology,
phenomena”. Among the studies found, we considered only those provided with discrete numerosity or clearly
Keywords:
Chronobiology
stated methodological characteristics.
Chronotherapy Results: The results of available studies were given, along with a series of short take-home messages at the end
Circadian rhythm of each mini-chapter devoted to: antihypertensives, statins, anticoagulants, analgesics, drugs for acid-related
Disease disorders, and anti-asthmatic drugs. In particular, evidence of morning vs. evening administration, when appli-
Internal medicine cable, was given for each medication.
Conclusions: Adequate evidence seems to support that at least ACE-inhibitors or angiotensin receptor blockers,
simvastatin, corticosteroids (slow-release formulation) for arthritic patients, and ranitidine should preferably
be administered in the evening. Morning dosing could be better for proton pump inhibitors, whereas time of
administration is not crucial for asthma inhalation drugs. Studies are available for other drugs, but not so strong
enough to draw definite conclusions. For now, we need prospective intervention trials specifically designed to
investigate the long-term effects of a temporal approach to medical therapy. However, since switching to
morning–evening administration or vice versa is simple and inexpensive, in some cases it could be considered,
remembering that, in any case, adherence remains the crucial point.
© 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction in the suprachiasmatic nucleus (SCN), is entrained by light and is sup-

Chronobiology is a branch of biomedical sciences devoted to the
study of biological rhythms. Biological rhythms exist at any level of
living organisms and, according to their cycle length, may be divided
into three main types: a) circadian rhythms (period of approximately
24 h), b) ultradian rhythms (period shorter than 24 h, e.g., hours, mi-
nutes, or even seconds), and c) infradian rhythms (period longer than
24 h, e.g., days, weeks, months, and seasons). Circadian rhythms are
the most commonly and widely studied biological rhythms, and are
driven by circadian clocks. Circadian clocks can be defined as a tran-
scriptionally based molecular mechanism, composed of both positive
and negative feedback loops, with a free-running period of approxi-
mately 24 h [1]. The principal circadian clock or master clock, located
⁎ Corresponding author at: Clinica Medica, Azienda Ospedaliera-Universitaria, Via
Aldo Moro 8, 44124 Cona (Ferrara), Italy. Tel.: +39 0532 237166; fax: +39 0532
236816.
E-mail addresses: degiorgialfredo@libero.it (A. De Giorgi),
ales.mallozzimenegat@student.unife.it (A. Mallozzi Menegatti), fabio.fabbian@unife.it
(F. Fabbian), francesco.portaluppi@unife.it (F. Portaluppi), roberto.manfredini@unife.it
(R. Manfredini).
posed to entrain peripheral clocks via neurohumoral modulation [1].
Circadian clocks have been identified within almost all mammalian
cell types, including vascular smooth muscle cells, endothelial cells
and cardiomyocytes [2], and circadian clock genes are essential for
cardiovascular health. Anticipation is the principal role of cellular bio-
logical clocks, since the capacity to know the time of day represents
critical information and selective advantage. The Circadian Time
Structure (CTS) encompasses the entirety of the body's circadian bio-
logical rhythms [3]. In particular, for example, the cardiovascular sys-
tem is organized according to a specific oscillatory temporal order,
and most cardiovascular functions exhibit circadian changes. Such
predictable-in-time differences in the physiological status of the
cardiovascular system give rise both to rhythmic variations in the
susceptibility of human beings to morbid and mortal events [4]. The
prominent CTS of human beings gives rise to important biological
time-dependent differences during the 24 h in the response to a
variety of clinical and laboratory diagnostic tests, risk of acute severe
medical events, symptom severity of a great number of medical dis-
eases, and positive or negative effects of medications. It is possible
that a given medication may be therapeutic and safe when administered

0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ejim.2013.03.019
 A. De Giorgi et al. / European Journal of Internal Medicine 24 (2013) 698–706 699

Table 1
Available studies on morning vs. evening schedule of dosing, focused on some relevant classes of drugs commonly used by internists. The principal characteristics of the studies, and
the appropriate reference number, are also provided.

Drugs

Better in the Better in the No difference

morning evening

Antihypertensive drugs
Ace-inhibitors & angiotensin receptor blockers (arbs)
Ramipril [9] X
(n = 115, randomized, morning vs. evening)
Enalapril [10] X
(n = 8, randomized, crossover, morning vs. evening)
Zofenopril [11] X
(n = 33, randomized, crossover, morning vs. evening)
Benazepril [12] X
(n = 10, single-blind, crossover, morning vs. evening)
Perindopril [13] X
(n = 20, randomized, crossover, morning vs. evening)
Olmesartan [14] X
(n = 123, randomized, morning vs. evening)
Valsartan [15] X
(n = 90, randomized, morning vs. evening)
Telmisartan [16] X
(n = 215, randomized, morning vs. evening)
Calcium channel blocker (CCB)
Nifedipine GITS [17] X
(n = 80, randomized, morning vs. evening)
Nifedipine GITS [18] X
(n = 180, randomized, morning vs. evening)
Amlodipine [19] X
(n = 12, open, randomized, crossover, morning vs. evening)
Amlodipine [20] X
(n = 20, open, randomized, placebo-controlled, morning vs. evening)
Isradipine SRO [21] X
(n = 16, double-blind, randomized, crossover)
Nisoldipine ER [22] X
(n = 85, randomized, crossover)
Diuretics
Torasemide [23] X
(n = 113, randomized, morning vs. evening)
β- & α-blockers
Nebivolol [24] X
(n = 42, randomized, double-blind, crossover, morning vs. evening)
Propanolol [25] X
(n = 44, randomized, crossover, morning vs. evening)
Doxazosin [26] X
(n = 111, randomized, no medication vs. evening dosing)
Combinations
Amlodipine/olmesartan [27] X
(n = 31, open-label, randomized, crossover, morning vs. evening)
Amlodipine/valsartan [28] X
(n = 203, randomized, both medications single or together, and morning vs. evening)
Hydrochlorothiazide/amlodipine [29] X
(n = 80, randomized, morning vs. evening)
Hydrochlorothiazide/valsartan [30] X
(n = 204, randomized, open-label, blinded-endpoint, morning vs. evening)
Amlodipine/valsartan [31] X
(n = 232, multicenter, prospective, randomized, open-label, blinded-endpoint,
morning vs. evening)
Hydrochlorothiazide/captopril [32] X
(n = 12, randomized, morning vs. evening)
Statins
Simvastatin [35] X
(n = 172, double-blind, placebo-controlled, morning vs. evening)
Simvastatin [36] X
(n = 60, randomized, morning vs. evening)
Fluvastatin ER [37] X
(n = 197, prospective, double-blind, multicenter, multiple dose)
Fluvastatin ER [38] X
(n = 26, randomized, 2-period crossover, morning vs. evening)
Atorvastatin [39] X
(n = 16, randomized, morning vs. evening)
Atorvastatin [40] X
(n = 64, randomized, morning vs. evening)
Rosuvastatin [41] X
(n = 24, open-label., 2-way crossover, morning vs. evening)
X

(continued on next page)

700 A. De Giorgi et al. / European Journal of Internal Medicine 24 (2013) 698–706

Table 1 (continued)
Drugs

Better in the Better in the No difference

morning evening

Ezetimibe–simvastatin [44]
(n = 171, multicentric, open-label, randomized, crossover)
Anticoagulants and antiaggregants
Sodium heparin [50] X
(n = 6, IV by constant pump infusion, morning vs. evening differences of PTT, TT, Xa)
Nadroparin [51] X
(n = 10, randomized, 6 am–12 am–6 pm–12 pm)
Deltaparin [52] X
(n = 10, open, 3-period crossover, morning vs. evening)
Warfarin [53] X
(n = 12, randomized, afternoon dosing, 6 pm)
Warfarin [54] X
(n = 30, morning dosing, four time points INR controls)
Analgesics
Paracetamol [63] X
(n = 8, open, crossover, 3 dosing times: 8 am, 2 pm, 8 pm)
Paracetamol [64] X
(n = 7, open, crossover, 3 dosing times: 7.30 am, 1 pm, 9 pm)
Ketoprofen [65] X
(n = 8, randomized, crossover, 4 dosing times: 7 am, 1 pm, 9 pm, 1 am)
Ketoprofen [66] X
(n = 117, double-blind, randomized, parallel-group, morning vs. evening)
Indomethacin [67] X
(n = 9, randomized, 5 dosing times: 7 am, 11 am, 3 pm, 7 pm, 11 pm)
Indomethacin [68] X
(n = 66, double-blind, crossover, 3 dosing times: 8 am, 12 am, 8 pm)
Corticosteroids (for arthritic pain)
Prednisone modified-release [70]
(n = 288, multicenter, randomized, double-blind)
Morphine [71] X
(n = 46, patient-controlled analgesia machine, control of dosing rates)
Morphine [72] X
(n = 61, open, check for extra-doses)
Morphine [73] X
(n = 40, as-needed basis administration, check for number and times of administrationas
Tramadol [77] X
(n = 18, controlled, randomized, double-blind, 6-fold, crossover, morning vs. evening)
Acid-related disorders drugs
Ranitidine [80] X
(n = 8, open, morning vs. evening)
Ranitidine [81] X
(n = 12, randomized, double-blind, placebo-controlled, morning vs. evening)
Lansoprazole [82] X
(n = 18, randomized, placebo-controlled, crossover, morning vs. evening)
Lansoprazole [83] X
(n = 32, double-blind, placebo-controlled, morning vs. evening)
Omeprazole [84] X
(n = 6, morning vs. evening)
Pantoprazole [85] X
(n = 12, randomized, double-blind, 2-period crossover, morning vs. evening)
Tenatoprazole [86] X
(n = 12, randomized, 3-period crossover, 7 am and 7 pm fasting, 9.30 am fed)
Bronchial asthma
Corticosteroids
Prednisolone [89] X
(n = 7, double-blind, placebo-controlled, crossover, dosing at 8 am, 3 pm, 8 pm)
Triamcinolone [90] X
(n = 30, randomized, 800mcg 3 pm vs. 200mcg four-times-a-day)
Beclometasone [91] X
(n = 42, randomized, double-blind, 3 regimens: morning + bedtime/morning/bedtime)
Mometasone [92] X
(n = 268, multicenter, placebo-controlled, evening vs. twice daily)
Budesonide [93] X
(n = 24, randomized, four treatments placebo-controlled, morning vs. evening)
Beta(2)-adrenergic agonists
Salmeterol [94] X
(n = 41, two-center, double-blind, randomized, crossover, evening vs. twice/day)
Formeterol, salmeterol, salbutamol [95] X
(n = 30, single-centre, double-blind, randomized, single-dose, crossover randomized, double-blind, placebo-controlled)
Corticosteroids and beta(2)-adrenergic agonists
Budesonide/formoterol [96] X
(n = 20, double-blind, placebo-controlled, crossover, evening vs. twice/day)
Anticholinergic drugs
X
 A. De Giorgi et al. / European Journal of Internal Medicine 24 (2013) 698–706
Table 1 (continued)
Drugs
Tiotropium [97]
(n = 121, double-blind, randomized, placebo controlled)
Leukotriene receptor antagonists
Montelukast [98]
(n = 343, randomized, placebo-controlled, multicenter, parallel-group, dose-ranging)
Montelukast [99]
(n = 24, randomized, crossover, morning vs. evening)
at some biological time, but subtherapeutic or poorly tolerated at
another time [3]. The aim of this narrative review is to describe the ev-
idence accumulated for the time-dependent aspects of major medical
conditions and to generate some hypotheses for the everyday practice
in internal medicine.
2. Methods
We arbitrarily decided to focus on some classes of drugs, widely
used by the internists: antihypertensives, statins, anticoagulants, anal-
gesics, drugs for acid-related disorders, and anti-asthmatic drugs. We
performed a PubMed search with the single classes of drugs associated
with the MeSH terms “Chronotherapy”, “Circadian rhythm”, and
“Chronobiology, phenomena”. Among the variety of studies found, we
decided to choose only those provided with discrete numerosity or
clearly stated methodological characteristics. Some of these informa-
tion, such as number of cases, randomization, single or double-blind,
single center or multicenter, crossover, dosage, have been indicated
for each study, so that each reader could evaluate either clinical rele-
vance or strength of conclusions. At the end of each mini-chapter, on
the basis of personal opinion, some brief take-home messages have
been also provided. Table 1 summarizes the studies with their main
characteristics, the appropriate reference indications, and the evidence
of some preference for morning or evening dosing, if applicable. The
majority of studies, in fact, is oriented to evaluate morning vs. evening
dosing schedules, probably also due to easier and relatively not so
much expensive protocols of studies, and a very few studies are avail-
able on drugs to be administered more than one only time daily.
2.1. Antihypertensive drugs
The circadian pattern of blood pressure (BP) has been known for
long time. Daily BP changes are due to normal activity (such as physical
activity, stress and posture), environmental phenomena (such as tem-
perature, humidity, and noise) and neuronal, endocrine, or hemody-
namic alterations [5]. These variations induce a BP pattern with two
peaks during the day (around 9 a.m. and 7 p.m.) and a nocturnal drop
around 3 a.m., with a physiological reduction of 10–20% from daytime
(awake) levels. An impairment in the nocturnal BP dip is an important
prognostic indicator of cardiovascular morbidity and mortality [6]. The
dipping status could be defined as diurnal/nocturnal BP ratio, and is cal-
culated as [100 × (BPdaytime mean − BP nighttime mean) / BPdaytime mean].
This formula classifies hypertensive patients as normal dippers, ex-
treme dippers, non-dippers and risers [3] with different CV risk. The
24-hour pattern of BP closely resembles the circadian variation in
onset of different cardiovascular diseases, e.g., stroke, acute myocardial
infarction, ventricular arrhythmias, arterial embolism and sudden car-
diac death [7,8], suggesting a causative or favoring role. Nevertheless,
how the effect of antihypertensive drugs may impact this BP pattern
is still a matter of debate.
2.1.1. Angiotensin inhibitors
Several papers showed different effects on BP values depending on
the time of administration of angiotensin converting enzyme inhibitors
701
Better in the Better in the No difference
morning evening
X
X
(ACE-inhibitors). In fact, evening doses of ramipril [9], enalapril [10],
zofenopril [11], benazepril [12], and perindopril [13] induce a higher
nighttime BP dip, followed by a slower increase during the day. Evening
administration of ACE-inhibitors can lower BP values at night condi-
tioning a significant modification of BP circadian pattern toward a
more physiological profile. Similar results were found in several studies
analyzing the effects of angiotensin receptor blockers (ARBs) [14–16]. A
normalization of the circadian BP profile toward to more physiological
pattern was shown only when the ARBs were administered at bedtime.
These drugs influence the activity peak of renin–angiotensin–aldoste-
rone system (RAAS) and then reduce the nocturnal BP values.
2.1.2. Calcium channel blockers
Hermida et al. [17,18] studied nifedipine GITS (gastro-intestinal
therapeutic system that releases the drug at the level of the intestinal
tract with a constant frequency) and showed that this leads to a better
BP control when taken at bedtime. Evening dose of nifedipine GITS
compared to early morning was more effective in reducing the BP
values in the early morning hours, at high risk of cardiovascular events
[8]. Dihydropyridine calcium channel blockers (CCB) reduce uniformly
the BP during the day and night, regardless of their time of administra-
tion, and several studies showed that the effectiveness of amlodipine on
BP reduction was independent from the time of administration [19,20].
Evening dosing of sustained-release oral (SRO) formulation of
isradipine led to reset of normal synchronization of the 24-h BP and
HR profile in renal patients with nocturnal hypertension [21], whereas
morning dosing of nisoldipine extended-release (ER) produced smaller
increases in sleep and early morning HR, in front of comparable hypo-
tensive effects, in patients with mild-to-moderate hypertension [22].
2.1.3. Diuretics
Torasemide (loop diuretic with long duration of action) and
hydrochlorothiazide showed a better effect on BP pattern after bed-
time dose [23].
2.1.4. Beta- and alpha-blockers
Nebivolol had a higher effectiveness after the evening dose com-
pared to morning administration [24]. Same results have been reported
for propanolol [25]. Again, evening administration of α-blockers
showed a maximal hypotensive effect in the early hours of the morning,
when vascular tone is enhanced [26].
2.1.5. Associations
The association ARBs/CCB showed a higher effectiveness for bedtime
than morning administration [27,28]. Same results were demonstrated
for hydrochlorothiazide/amlodipine [29] and hydrochlorothiazide/
valsartan [30]. On the contrary, Asmar et al. [31] did not find significant
differences between morning vs evening dose of valsartan/amlodipine.
The association ACE-inhibitor/diuretics was more effective after
morning administration [32]. Patients with chronic kidney disease
(CKD) and type 2 diabetes mellitus showed a non-dipper BP pattern
more frequently then the essential hypertensives and these patients
get a better BP pattern after bedtime administration of antihypertensive
drugs [33,34].
702 A. De Giorgi et al. / European Journal of Internal Medicine 24 (2013) 698–706
Take-home message
Evidence is accumulating that a bedtime dosing of antihypertensive
drugs can lower BP values at night (e.g. non dipper hypertensives) or,
at least, favor significant modification of BP circadian pattern towards
a more physiological profile. The choice of time of dosing might be tai-
lored on each person and, when more than one medication is given, at
least one (ACE-inhibitor or ARB) should be prescribed as evening dose.
2.2. Statins
Statins are the main therapy in hypercholesterolemia. Their phar-
macological effect is given by inhibition of hydroxymethylglutaryl co-
enzyme A (HMG-CoA) reductase, inducing the interruption of liver
cholesterol biosynthesis, the expression of LDL-receptors binding cir-
culating LDL-cholesterol (LDL-c), with the result of a reduction of
plasma levels of LDL-c.
Different molecules have different bioavailability: simvastatin,
lovastatin and atorvastatin are hydrophilic molecules, unlike the
others that are lipophilic. These latter must be metabolized in hydro-
philic compounds to be more easily excreted in the urine. Few trials
have evaluated the chronopharmacological feature of statins. In the
first placebo-controlled, double-blind study comparing the effective-
ness of morning versus evening administration of simvastatin [35],
the reduction in total cholesterol (TC) levels was greater in patients
taking simvastatin in the evening than in the morning (−15.4% vs.
− 10.9% for simvastatin 2.5 mg, − 20.7% vs 13.7% for simvastatin
5 mg). High density lipoprotein cholesterol (HCL-c) and triglycerides
(TG) levels did not show any changes. Further evidence comes from
Wallace et al. [36] who reported a significant increase of LDL-c levels
in patients who switched simvastatin from evening to morning.
Time-dependent effectiveness of fluvastatin extended-release (ER)
was evaluated by Scharnagl et al. [37] and Fauler et al. [38], and
there were no statistically significant differences between morning
and evening treatment groups. As for atorvastatin, no significant dif-
ferences after morning or evening administration were reported by
Cilla et al. [39] and Plakogiannis et al. [40]. Also rosuvastatin [41]
did not show significant differences in lipid serum levels for morning
versus evening administration. No studies with statistically signifi-
cant results are available for pravastatin (hydrophilic) and lovastatin
(lipophilic). Only, lovastatin has been shown to affect daytime perfor-
mance, in particular attention and vigilance, that worsened significantly
from baseline as did global performance, whereas pravastatin did not
[42]. In conclusion, there are sufficient data to support evening admin-
istrations of simvastatin only, to achieve optimal lowering of LDL-c
levels [43]. Again, also for ezetimibe, a drug that inhibits cholesterol ab-
sorption by limiting the passage of cholesterol of dietary and biliary or-
igin across the intestinal wall, in association with simvastatin, no
significant differences were found between LDL-c reduction after morn-
ing or evening administration (46% vs. 48%, respectively) [44].
Take-home message
Since the economic burden strongly suggests the use of off-patent
drugs, simvastatin administration is recommended in the evening, al-
so considering that the endogenous production of cholesterol is
higher at night. It could be that night administration induces a major
pharmacological effect of these drugs when cholesterol levels are
higher. As for more potent statins (e.g., atorvastatin, rosuvastatin,
and association simvastatin/ezetimibe), there is no significant differ-
ence between morning and evening dose.
2.3. Anticoagulants and antiplatelets
Acute thromboembolic events such as pulmonary embolism, acute
myocardial infarction and stroke occur more frequently in the early
hours of the day [45–47]. Circadian variations were found in different
plasma components involved in the hemostasis, with morning
peaks for platelet adhesiveness [48], fibrinogen concentrations, and
activated factor VII, factor VIII and factor IX [49]. However, despite
these data on circadian variations, very few data are available on pos-
sible time-effects of anticoagulants and antiplatelet drugs.
2.3.1. Heparins
A circadian variation of the anticoagulant effect of unfractioned
heparin was reported by Decousus et al. [50], with maximum during
the night and minimum in the morning, and significant percentage
changes by about 50%. As for the newest low molecular weight hepa-
rins (LMWH), Mismetti et al. [51] found that a single subcutaneous
bolus of nadroparine (7500 UI) induced higher anti-Xa activity after
12 a.m. injection, with no difference on APTT values. The same author
performed the same test with deltaparin, showing a greater increase
of activated partial thromboplastin time (aPTT), thrombin time (TT),
prothrombin time (PT) and tissue factor pathway inhibitor (TFPI)
after 8 p.m. dose [52].
2.3.2. Warfarin
Bleske et al. [53] found a peak of INR between 4 a.m. to 8 a.m.
when warfarin was assumed at 6 p.m., and Ho et al. [54] did not de-
tect significant change in INR was given between 7 a.m. and 9 a.m.
As for aspirin, an evening dosing has been theoretically suggested
to optimize its pharmacological effect [55], but no studies have been
performed.
Take-home messages
The very limited number of studies, with smallest size of population,,
does not allow to draw any conclusion. Thus, given the actual level of
knowledge, we believe that the current schedule of administration
(morning or afternoon prophylactic dose for low-molecular-weight-
heparin, afternoon dose for warfarin) is valid.
2.4. Analgesics
Many studies have been conducted over the years on the time-
dependent variation in perception of pain, its neurochemistry, and
pharmacological treatment. It seems now evident that the intensity
of pain varies depending on time of day, even if it should always be
kept in mind that night hours and reduced sleep time may be associ-
ated with diminished analgesic benefits from distraction [56]. Any-
way, the evaluation of the profile of daily pain should be used to
determine the best time for analgesic administration, in order to im-
prove pain treatment. Arthritic pain respects a circadian rhythm. Pa-
tients with rheumatoid arthritis usually indicate the presence of
greatest pain in the morning [57], and a significant circadian rhythm
has been reported for hand osteoarthritis, characterized by least pain
and stiffness and peak of dexterity in the early afternoon hours [58].
Levels of endogenous opioid peptides have been shown to be higher
early in the day and reduced at night [59], and higher levels of methi-
onine enkephalin-like, substance P-like and beta-endorphin have
been shown as well [60]. However, the circadian rhythm of beta-
endorphin was altered in cancer patients compared to healthy sub-
jects [61]. It is likely that circadian variations in the perception of
pain, and the efficacy and toxicity of analgesic drugs, may influence
their efficiency and/or the tolerance especially in the treatment of
acute pain.
2.4.1. Placebo
Pain is a subjective symptom, and psychological factors are often
involved. Thus, it is not surprising that analgesia produced by placebo
varies depending on time of administration. In healthy volunteers
 A. De Giorgi et al. / European Journal of Internal Medicine 24 (2013) 698–706
with dental pain, the effect of a placebo was significantly more effec-
tive (increase of pain threshold of 25–30%) when ingested during the
day (9 a.m. to 10 p.m.), and rather null in the late evening [62].
2.4.2. Paracetamol (acetaminophen)
Although changes in circadian analgesic efficacy of paracetamol
have not been documented by clinical studies, Malan et al. [63] did
not find significant difference in its time of administration, and
Kolawole et al. [64] found that a midday dose of acetaminophen in-
duced an increased half-life due to lower clearance.
2.4.3. NSAIDS
Bioavailability of NSAIDs is greater in the morning. Plasma levels
of indomethacin or ketoprofene after ingestion at 7 a.m. were about
50–58% greater compared with evening dose [65,66]. In addition,
the absorption phase of NSAIDs in the morning was greater and faster
than in the evening [67,68]. The time of dosing with optimal effec-
tiveness differed among subjects, maybe due to large interindividual
differences in the circadian variation of self-rated pain intensity. Eve-
ning dosing was most effective in subjects with predominantly noc-
turnal or morning pain; conversely, morning or noon dosing was
most effective in subjects with greater afternoon or evening pain.
Kowanko et al. [57] in a study on patients with rheumatoid arthritis
(RA), showed that a dose of 100 mg of flurbiprofen administered
twice daily was more effective than a dose of 50 mg ingested four
times daily. However, subjective measures of pain and stiffness indi-
cated that one of the two doses of drug had to be taken during the
night, in order to control effectively the morning stiffness and pain.
As for adverse effects, they could be higher when the drugs were
ingested in the morning. Moore et al. [69], in fact, observed that the
number of gastric lesions produced by oral administration of 1 g of
ASA at 10 a.m. was twice that the number of lesions produced by
oral administration of the same dose at 10 p.m.
2.4.4. Corticosteroids
As reported before, patients with rheumatoid arthritis usually in-
dicate the presence of greatest pain in the morning [57]. Thus, a
new modified-release delivery system adapting the release of the ad-
ministered glucocorticoid to the circadian rhythms of endogenous
cortisol and disease symptoms, has been developed. A multicenter,
randomized, double-blind trial, was conducted in patients with active
rheumatoid arthritis, who were assigned to either a modified-release
prednisone tablet (taken at bedtime) or to an immediate-release
prednisone tablet (morning administration) [70]. Bedtime adminis-
tration of modified-release prednisone was well tolerated, convenient
to administer, and produced a clinically relevant reduction of morn-
ing stiffness of the joints (− 22%). Of course, it has to be stressed
that the circadian rhythm of corticosteroids has been established
many decades ago. Thus, corticosteroids should be administered in
the morning, in the respect of such circadian rhythm, and the evening
dosing schedule (of a slow released formulation) should be limited to
arthritic patients.
2.4.5. Opioids
Morning seems to be the temporal window where opioids are most
required, at least in conditions of post-surgery intervention [71]. In fact,
self-administration of morphine was near 50% higher during the day
than during night [72]. Again, in patients with cancer pain, the distribu-
tion of extra-doses of narcotic analgesics was 60% lower during the
night than during the day [73], suggesting that the circadian distribu-
tion of the use of narcotic analgesics is probably an indirect evidence
of the circadian rhythm of pain intensity. It is interesting to note that
a different body's circadian sensitivity to opioids has been suggested
in a study dealing with opioid overdose [74]. It has been stressed, how-
ever, that an intra-individual variation of in morphine absorption, pro-
duction of the active metabolite morphine-6-glucuronide, and the
703
volume of distribution during the day, exists since a variability of plas-
ma morphine concentrations after oral administration has been docu-
mented in patients with severe cancer pain [75]. Again, an evening
dose of fentanyl induced a higher reduction of patients' pain visual an-
alog score [76]. As for tramadol, Hummel et al. [77] found no difference
in plasma drug levels depending on the time of administration, but the
analgesic effect was stronger after evening dose.
Take-home messages
Pain is a complex phenomenon, not only due to the release of biochem-
ical factors in response to tissue damage but also related to different in-
dividual factors such as anxiety, fatigue, distraction, suggestions and
previous experiences. All this makes the pain condition extremely
subjective. The aim of the chronotherapeutic strategy is to ensure that
patients receive maximum analgesia with minimal side effects. The
limited number of studies on this topic, the existence of circadian vari-
ations in the intensity of pain, and the interindividual differences, do
not provide definite conclusions and suggest for tailored schedules.
2.5. Drugs for acid-related disorders
The gastrointestinal tract works following a biologic rhythm re-
garding basal gastric acid output, epithelial cell proliferation, gastro-
intestinal motility, and appetite regulation. The circadian pattern of
gastric pH is characterized by a peak during early evening (6 p.m.–
10 p.m.), and a progressive reduction during the night [78], even
though significant differences in pH pattern may occur in healthy
controls and patients with duodenal ulcer patients. A particular entity
has been described as “nocturnal acid breakthrough”, defined as gas-
tric pH lower than 4 lasting for at least 60 consecutive minutes in the
overnight period (10 p.m. to 6 a.m.) [79].
2.5.1. H2-receptor antagonists
Ranitine, given during night-time, was associated with a higher
inhibition of intragastric acidity either in healthy subjects [80], and
in patients with duodenal ulcer with nocturnal acid breakthrough
[81].
2.5.2. Proton pump inhibitors (PPI)
Plasma levels of lansoprazole were higher after morning dose [82],
and morning doses were associated with a higher effect on gastric pH
than evening doses [83]. Similar results were found for omeprazole
[84] and pantoprazole [85]. There are no significant changes in the
gastric pH levels according to time-dependent administration of
tenatoprazole, although morning doses were associated with higher
drug plasma concentrations [86]. In this respect, it should be noted
that higher plasma levels of a drug do not necessarily correspond to
synchronous higher therapeutic effects. Keeping in mind that gastric
pH is always much lower at night (the longest period of the day
when no food is ingested, leaving gastric acidity unbuffered), what
really counts on a clinical basis is the net effect on nocturnal pH in-
duced by the different temporal administrations of antiacid drugs.
Take-home messages
A time-dependent efficacy of different drugs has been shown in sever-
al studies, and a practical suggestion could be to use PPIs in the morn-
ing and H2 receptor antagonists in the evening.
2.6. Bronchial asthma
Chronobiological patterns of allergic rhinitis (AR) and bronchial
asthma (BA) are known since three decades [87], with symptoms
704 A. De Giorgi et al. / European Journal of Internal Medicine 24 (2013) 698–706
related to AR developing more frequently in the morning than
the remaining part of the day, and exacerbations of asthma being
more frequent during the night. The well known nocturnal parasym-
pathetic activity with consequent reduced bronchial caliber and
raised airway resistance, the greater amount of inflammatory cell,
together with a lower function of neuroendocrine (hypothalamic–
pituitary–adrenocortical) system, are all important factors responsi-
ble of the higher incidence of asthma during the night, including
early morning hours.
2.6.1. Corticosteroids
A pioneeristic study evaluating the relationship between cortico-
steroid therapy and time of administration [88] found that a dose
of methyl-prednisolone (40 mg) was more effective on peak
expiratory flow rate (PEFR) when administrated at 3 p.m., and less
effective at 3 a.m. and 7 p.m. The authors reported a reduction of
biomarkers of inflammation, evaluated by blood eosinophil and
pancellular bronchoalveolar lavage cytology. Further confirmations
came from Beam et al. [89], who treated patients with oral dose of
prednisone at 8 a.m., 3 p.m. and 8 p.m., obtaining an increase of
FEV1 and decreasing inflammation (compared to placebo) in the
group receiving the drug at 3 p.m. Again, Pincus et al. [90] showed
that a single dose of corticosteroid administered at 3 p.m. was more
effective in improving FEV1 than the 4 doses of 200 μg. As for
inhaled corticosteroids, no significant differences were found among
3 treatments: 500 μg of inhaled beclomethasone twice-daily, or
1000 μg in the late afternoon or 1000 μg at bedtime [91]. Similar re-
sults were found with mometasone furoate [92] and budesonide [93].
2.6.2. Beta2-adrenergic agonists
A study on patients with poorly controlled nocturnal asthma,
showed that a single dose of salmeterol 100 μg given in the evening
had the same effect compared with two daily doses of 50 μg, even if
evening administration was associated with higher FEV1 [94]. Similar
results on bronchodilation were obtained with different types of
beta2-adrenergic agonist drugs (formoterol 24 μg, 50 μg salmeterol
and salbutamol 200 μg) [95]. The evening dose of combined cortico-
steroids and beta2-adrenergic agonists was better than the morning
dose in improving FEV1 and maximum expiratory flow at 25–75% of
forced vital capacity (MEF25–75%) [96].
2.6.3. Anticholinergics
Although cholinergic tone is increased during the night, a double
blind, randomized, placebo controlled trial in patients with stable
chronic obstructive pulmonary disease (COPD), treated with
tiotropium once daily in the morning (9 a.m.) or in the evening
(9 p.m.), or an identical placebo doses, showed that there were no
significant differences in the morning versus evening administration
[97].
2.6.4. Leukotriene receptor antagonists
Cysteinyl leukotrienes are derivatives of arachidonic acid metabo-
lism, and are important mediators of airway inflammation. Among
these, montelukast is one of the most widely used leukotriene recep-
tor antagonists. Although a first study reported a higher effectiveness
after evening administration [98], another study [99] failed to find
significant differences in its effect depending on morning versus eve-
ning administration.
Take-home messages
Although, in line of principle, bronchodilators are preferred for diur-
nal dosing and anti-parasympathetic drugs for evening dosing, no
definite conclusions can be drawn from the available evidence. In
particular, in the case of drugs administrated by inhalation, their
effects appear to be independent of time of administration.
3. Conclusions
In clinical practice, time of drug administration often matters, i.e. it
is bound to affect the efficacy and side effects of many medications. In
this respect, some drug classes have been extensively studied (like
ACE-inhibitors, ARBS, alpha- and beta-blockers in hypertension, corti-
costeroids and beta2-adrenergic agonists in asthma, simvastatin,
drugs for acid-related disorders), others have been studied with in-
complete or contrasting results (pain killers and anticoagulants),
many more still remain to be investigated. As summarized above, for
some molecules we have clear indications that the most favorable
time of administration is either the morning or the evening (very sel-
dom, studies are available comparing other times of administration).
Moreover, some evidence indicates the possibility that a preferred
time of administration is molecule specific in some cases, and
class-specific in others. In any case, the applicability of such aspects
to clinical practice is often limited also by individual factors, such as
normal synchronization or desynchronization of the individual CTS,
induced by different lifestyles or even by disease itself, like it often
happens in cancer patients. Altogether, the above characteristics ap-
pear to limit the generalization of a temporal prescription of many
drugs. Again, we do not know enough about the effect or interactions
of polypharmacy, and, especially in elderly patients assuming multiple
medications, whether the most appropriate “circadian” administra-
tion could be in tune (or be against) the risk of pharmacological inter-
actions. While we have to wait for prospective intervention trials
specifically designed to investigate the long-term effects of such
a temporal approach to therapy in many diseases, although some
recent studies provided convincing preliminary evidence that a
chronotherapeutic approach with antihypertensive medications is as-
sociated with a significant reduction of cardiovascular events [33,34],
we already have reasons to compare in our individual patients the dif-
ferences in efficacy and side effects often documentable between
morning and evening administration. Since such switch represents
simple and inexpensive procedure, which in turn may result in dra-
matic improvements or worsenings in efficacy and/or adherence to
therapy, we believe that this is a promising field which deserves fur-
ther investigation aimed to obtain precious indications on how to op-
timize the temporal aspects of drug administration. In any way,
accurate adherence to pharmacological schedules is the crucial point
for the clinical success of a therapy, and it should be always pursued.
Learning points
• Chronobiology is a branch of biomedical sciences devoted to the
study of biological rhythms, and circadian rhythms are the most
commonly and widely studied.
• According to body rhythms, it is possible that a given medication
may be therapeutic and safe when administered at some biological
time, but subtherapeutic or poorly tolerated at another time.
• In clinical practice, time of drug administration often matters, i.e. it
is bound to affect the efficacy and side effects of many medications.
• Some evidence indicates the possibility that a preferred time of ad-
ministration is molecule specific in some cases, and class-specific in
others. ACE-inhibitors or angiotensin receptor blockers, simvastat-
in, corticosteroids (slow-release formulation) for arthritic patients,
and ranitidine should preferably be administered in the evening.
Morning dosing could be better for proton pump inhibitors, where-
as time of administration of inhalation medications for asthma is
not crucial.
• Studies are available also for other drugs, but the evidence is not
strong enough to draw definite conclusions. Prospective interven-
tion trials specifically designed to investigate the long-term effects
of such a temporal approach to therapy in many diseases are
needed.
 A. De Giorgi et al. / European Journal of Internal Medicine 24 (2013) 698–706
Conflict of interests
None of the authors have any actual or potential conflict of inter-
est financial, personal, or otherwise that could influence or be per-
ceived to influence their work.
Financial support
This work has been supported, in part, by a scientific grant from
the University of Ferrara (FAR — Fondo Ateneo Ricerca) (Prof. Roberto
Manfredini).
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