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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-


posed to entrain peripheral clocks via neurohumoral modulation [1].
Chronobiology is a branch of biomedical sciences devoted to the Circadian clocks have been identified within almost all mammalian
study of biological rhythms. Biological rhythms exist at any level of cell types, including vascular smooth muscle cells, endothelial cells
living organisms and, according to their cycle length, may be divided and cardiomyocytes [2], and circadian clock genes are essential for
into three main types: a) circadian rhythms (period of approximately cardiovascular health. Anticipation is the principal role of cellular bio-
24 h), b) ultradian rhythms (period shorter than 24 h, e.g., hours, mi- logical clocks, since the capacity to know the time of day represents
nutes, or even seconds), and c) infradian rhythms (period longer than critical information and selective advantage. The Circadian Time
24 h, e.g., days, weeks, months, and seasons). Circadian rhythms are Structure (CTS) encompasses the entirety of the body's circadian bio-
the most commonly and widely studied biological rhythms, and are logical rhythms [3]. In particular, for example, the cardiovascular sys-
driven by circadian clocks. Circadian clocks can be defined as a tran- tem is organized according to a specific oscillatory temporal order,
scriptionally based molecular mechanism, composed of both positive and most cardiovascular functions exhibit circadian changes. Such
and negative feedback loops, with a free-running period of approxi- predictable-in-time differences in the physiological status of the
mately 24 h [1]. The principal circadian clock or master clock, located cardiovascular system give rise both to rhythmic variations in the
susceptibility of human beings to morbid and mortal events [4]. The
⁎ Corresponding author at: Clinica Medica, Azienda Ospedaliera-Universitaria, Via prominent CTS of human beings gives rise to important biological
Aldo Moro 8, 44124 Cona (Ferrara), Italy. Tel.: +39 0532 237166; fax: +39 0532 time-dependent differences during the 24 h in the response to a
236816. variety of clinical and laboratory diagnostic tests, risk of acute severe
E-mail addresses: degiorgialfredo@libero.it (A. De Giorgi),
ales.mallozzimenegat@student.unife.it (A. Mallozzi Menegatti), fabio.fabbian@unife.it
medical events, symptom severity of a great number of medical dis-
(F. Fabbian), francesco.portaluppi@unife.it (F. Portaluppi), roberto.manfredini@unife.it eases, and positive or negative effects of medications. It is possible
(R. Manfredini). 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) 698–706 701

Table 1 (continued)
Drugs

Better in the Better in the No difference


morning evening

Tiotropium [97]
(n = 121, double-blind, randomized, placebo controlled)
Leukotriene receptor antagonists
Montelukast [98] X
(n = 343, randomized, placebo-controlled, multicenter, parallel-group, dose-ranging)
Montelukast [99] X
(n = 24, randomized, crossover, morning vs. evening)

at some biological time, but subtherapeutic or poorly tolerated at (ACE-inhibitors). In fact, evening doses of ramipril [9], enalapril [10],
another time [3]. The aim of this narrative review is to describe the ev- zofenopril [11], benazepril [12], and perindopril [13] induce a higher
idence accumulated for the time-dependent aspects of major medical nighttime BP dip, followed by a slower increase during the day. Evening
conditions and to generate some hypotheses for the everyday practice administration of ACE-inhibitors can lower BP values at night condi-
in internal medicine. tioning a significant modification of BP circadian pattern toward a
more physiological profile. Similar results were found in several studies
2. Methods analyzing the effects of angiotensin receptor blockers (ARBs) [14–16]. A
normalization of the circadian BP profile toward to more physiological
We arbitrarily decided to focus on some classes of drugs, widely pattern was shown only when the ARBs were administered at bedtime.
used by the internists: antihypertensives, statins, anticoagulants, anal- These drugs influence the activity peak of renin–angiotensin–aldoste-
gesics, drugs for acid-related disorders, and anti-asthmatic drugs. We rone system (RAAS) and then reduce the nocturnal BP values.
performed a PubMed search with the single classes of drugs associated
with the MeSH terms “Chronotherapy”, “Circadian rhythm”, and 2.1.2. Calcium channel blockers
“Chronobiology, phenomena”. Among the variety of studies found, we Hermida et al. [17,18] studied nifedipine GITS (gastro-intestinal
decided to choose only those provided with discrete numerosity or therapeutic system that releases the drug at the level of the intestinal
clearly stated methodological characteristics. Some of these informa- tract with a constant frequency) and showed that this leads to a better
tion, such as number of cases, randomization, single or double-blind, BP control when taken at bedtime. Evening dose of nifedipine GITS
single center or multicenter, crossover, dosage, have been indicated compared to early morning was more effective in reducing the BP
for each study, so that each reader could evaluate either clinical rele- values in the early morning hours, at high risk of cardiovascular events
vance or strength of conclusions. At the end of each mini-chapter, on [8]. Dihydropyridine calcium channel blockers (CCB) reduce uniformly
the basis of personal opinion, some brief take-home messages have the BP during the day and night, regardless of their time of administra-
been also provided. Table 1 summarizes the studies with their main tion, and several studies showed that the effectiveness of amlodipine on
characteristics, the appropriate reference indications, and the evidence BP reduction was independent from the time of administration [19,20].
of some preference for morning or evening dosing, if applicable. The Evening dosing of sustained-release oral (SRO) formulation of
majority of studies, in fact, is oriented to evaluate morning vs. evening isradipine led to reset of normal synchronization of the 24-h BP and
dosing schedules, probably also due to easier and relatively not so HR profile in renal patients with nocturnal hypertension [21], whereas
much expensive protocols of studies, and a very few studies are avail- morning dosing of nisoldipine extended-release (ER) produced smaller
able on drugs to be administered more than one only time daily. increases in sleep and early morning HR, in front of comparable hypo-
tensive effects, in patients with mild-to-moderate hypertension [22].
2.1. Antihypertensive drugs
2.1.3. Diuretics
The circadian pattern of blood pressure (BP) has been known for Torasemide (loop diuretic with long duration of action) and
long time. Daily BP changes are due to normal activity (such as physical hydrochlorothiazide showed a better effect on BP pattern after bed-
activity, stress and posture), environmental phenomena (such as tem- time dose [23].
perature, humidity, and noise) and neuronal, endocrine, or hemody-
namic alterations [5]. These variations induce a BP pattern with two 2.1.4. Beta- and alpha-blockers
peaks during the day (around 9 a.m. and 7 p.m.) and a nocturnal drop Nebivolol had a higher effectiveness after the evening dose com-
around 3 a.m., with a physiological reduction of 10–20% from daytime pared to morning administration [24]. Same results have been reported
(awake) levels. An impairment in the nocturnal BP dip is an important for propanolol [25]. Again, evening administration of α-blockers
prognostic indicator of cardiovascular morbidity and mortality [6]. The showed a maximal hypotensive effect in the early hours of the morning,
dipping status could be defined as diurnal/nocturnal BP ratio, and is cal- when vascular tone is enhanced [26].
culated as [100 × (BPdaytime mean − BP nighttime mean) / BPdaytime mean].
This formula classifies hypertensive patients as normal dippers, ex- 2.1.5. Associations
treme dippers, non-dippers and risers [3] with different CV risk. The The association ARBs/CCB showed a higher effectiveness for bedtime
24-hour pattern of BP closely resembles the circadian variation in than morning administration [27,28]. Same results were demonstrated
onset of different cardiovascular diseases, e.g., stroke, acute myocardial for hydrochlorothiazide/amlodipine [29] and hydrochlorothiazide/
infarction, ventricular arrhythmias, arterial embolism and sudden car- valsartan [30]. On the contrary, Asmar et al. [31] did not find significant
diac death [7,8], suggesting a causative or favoring role. Nevertheless, differences between morning vs evening dose of valsartan/amlodipine.
how the effect of antihypertensive drugs may impact this BP pattern The association ACE-inhibitor/diuretics was more effective after
is still a matter of debate. morning administration [32]. Patients with chronic kidney disease
(CKD) and type 2 diabetes mellitus showed a non-dipper BP pattern
2.1.1. Angiotensin inhibitors more frequently then the essential hypertensives and these patients
Several papers showed different effects on BP values depending on get a better BP pattern after bedtime administration of antihypertensive
the time of administration of angiotensin converting enzyme inhibitors drugs [33,34].
702 A. De Giorgi et al. / European Journal of Internal Medicine 24 (2013) 698–706

Take-home message hours of the day [45–47]. Circadian variations were found in different
plasma components involved in the hemostasis, with morning
Evidence is accumulating that a bedtime dosing of antihypertensive peaks for platelet adhesiveness [48], fibrinogen concentrations, and
drugs can lower BP values at night (e.g. non dipper hypertensives) or, activated factor VII, factor VIII and factor IX [49]. However, despite
at least, favor significant modification of BP circadian pattern towards these data on circadian variations, very few data are available on pos-
a more physiological profile. The choice of time of dosing might be tai- sible time-effects of anticoagulants and antiplatelet drugs.
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. 2.3.1. Heparins
A circadian variation of the anticoagulant effect of unfractioned
2.2. Statins heparin was reported by Decousus et al. [50], with maximum during
the night and minimum in the morning, and significant percentage
Statins are the main therapy in hypercholesterolemia. Their phar- changes by about 50%. As for the newest low molecular weight hepa-
macological effect is given by inhibition of hydroxymethylglutaryl co- rins (LMWH), Mismetti et al. [51] found that a single subcutaneous
enzyme A (HMG-CoA) reductase, inducing the interruption of liver bolus of nadroparine (7500 UI) induced higher anti-Xa activity after
cholesterol biosynthesis, the expression of LDL-receptors binding cir- 12 a.m. injection, with no difference on APTT values. The same author
culating LDL-cholesterol (LDL-c), with the result of a reduction of performed the same test with deltaparin, showing a greater increase
plasma levels of LDL-c. of activated partial thromboplastin time (aPTT), thrombin time (TT),
Different molecules have different bioavailability: simvastatin, prothrombin time (PT) and tissue factor pathway inhibitor (TFPI)
lovastatin and atorvastatin are hydrophilic molecules, unlike the after 8 p.m. dose [52].
others that are lipophilic. These latter must be metabolized in hydro-
philic compounds to be more easily excreted in the urine. Few trials 2.3.2. Warfarin
have evaluated the chronopharmacological feature of statins. In the Bleske et al. [53] found a peak of INR between 4 a.m. to 8 a.m.
first placebo-controlled, double-blind study comparing the effective- when warfarin was assumed at 6 p.m., and Ho et al. [54] did not de-
ness of morning versus evening administration of simvastatin [35], tect significant change in INR was given between 7 a.m. and 9 a.m.
the reduction in total cholesterol (TC) levels was greater in patients As for aspirin, an evening dosing has been theoretically suggested
taking simvastatin in the evening than in the morning (−15.4% vs. to optimize its pharmacological effect [55], but no studies have been
− 10.9% for simvastatin 2.5 mg, − 20.7% vs 13.7% for simvastatin performed.
5 mg). High density lipoprotein cholesterol (HCL-c) and triglycerides
(TG) levels did not show any changes. Further evidence comes from Take-home messages
Wallace et al. [36] who reported a significant increase of LDL-c levels
in patients who switched simvastatin from evening to morning. The very limited number of studies, with smallest size of population,,
Time-dependent effectiveness of fluvastatin extended-release (ER) does not allow to draw any conclusion. Thus, given the actual level of
was evaluated by Scharnagl et al. [37] and Fauler et al. [38], and knowledge, we believe that the current schedule of administration
there were no statistically significant differences between morning (morning or afternoon prophylactic dose for low-molecular-weight-
and evening treatment groups. As for atorvastatin, no significant dif- heparin, afternoon dose for warfarin) is valid.
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 2.4. Analgesics
versus evening administration. No studies with statistically signifi-
cant results are available for pravastatin (hydrophilic) and lovastatin Many studies have been conducted over the years on the time-
(lipophilic). Only, lovastatin has been shown to affect daytime perfor- dependent variation in perception of pain, its neurochemistry, and
mance, in particular attention and vigilance, that worsened significantly pharmacological treatment. It seems now evident that the intensity
from baseline as did global performance, whereas pravastatin did not of pain varies depending on time of day, even if it should always be
[42]. In conclusion, there are sufficient data to support evening admin- kept in mind that night hours and reduced sleep time may be associ-
istrations of simvastatin only, to achieve optimal lowering of LDL-c ated with diminished analgesic benefits from distraction [56]. Any-
levels [43]. Again, also for ezetimibe, a drug that inhibits cholesterol ab- way, the evaluation of the profile of daily pain should be used to
sorption by limiting the passage of cholesterol of dietary and biliary or- determine the best time for analgesic administration, in order to im-
igin across the intestinal wall, in association with simvastatin, no prove pain treatment. Arthritic pain respects a circadian rhythm. Pa-
significant differences were found between LDL-c reduction after morn- tients with rheumatoid arthritis usually indicate the presence of
ing or evening administration (46% vs. 48%, respectively) [44]. greatest pain in the morning [57], and a significant circadian rhythm
has been reported for hand osteoarthritis, characterized by least pain
Take-home message and stiffness and peak of dexterity in the early afternoon hours [58].
Levels of endogenous opioid peptides have been shown to be higher
Since the economic burden strongly suggests the use of off-patent early in the day and reduced at night [59], and higher levels of methi-
drugs, simvastatin administration is recommended in the evening, al- onine enkephalin-like, substance P-like and beta-endorphin have
so considering that the endogenous production of cholesterol is been shown as well [60]. However, the circadian rhythm of beta-
higher at night. It could be that night administration induces a major endorphin was altered in cancer patients compared to healthy sub-
pharmacological effect of these drugs when cholesterol levels are jects [61]. It is likely that circadian variations in the perception of
higher. As for more potent statins (e.g., atorvastatin, rosuvastatin, pain, and the efficacy and toxicity of analgesic drugs, may influence
and association simvastatin/ezetimibe), there is no significant differ- their efficiency and/or the tolerance especially in the treatment of
ence between morning and evening dose. acute pain.

2.3. Anticoagulants and antiplatelets 2.4.1. Placebo


Pain is a subjective symptom, and psychological factors are often
Acute thromboembolic events such as pulmonary embolism, acute involved. Thus, it is not surprising that analgesia produced by placebo
myocardial infarction and stroke occur more frequently in the early varies depending on time of administration. In healthy volunteers
A. De Giorgi et al. / European Journal of Internal Medicine 24 (2013) 698–706 703

with dental pain, the effect of a placebo was significantly more effec- volume of distribution during the day, exists since a variability of plas-
tive (increase of pain threshold of 25–30%) when ingested during the ma morphine concentrations after oral administration has been docu-
day (9 a.m. to 10 p.m.), and rather null in the late evening [62]. mented in patients with severe cancer pain [75]. Again, an evening
dose of fentanyl induced a higher reduction of patients' pain visual an-
2.4.2. Paracetamol (acetaminophen) alog score [76]. As for tramadol, Hummel et al. [77] found no difference
Although changes in circadian analgesic efficacy of paracetamol in plasma drug levels depending on the time of administration, but the
have not been documented by clinical studies, Malan et al. [63] did analgesic effect was stronger after evening dose.
not find significant difference in its time of administration, and
Kolawole et al. [64] found that a midday dose of acetaminophen in- Take-home messages
duced an increased half-life due to lower clearance.
Pain is a complex phenomenon, not only due to the release of biochem-
2.4.3. NSAIDS ical factors in response to tissue damage but also related to different in-
Bioavailability of NSAIDs is greater in the morning. Plasma levels dividual factors such as anxiety, fatigue, distraction, suggestions and
of indomethacin or ketoprofene after ingestion at 7 a.m. were about previous experiences. All this makes the pain condition extremely
50–58% greater compared with evening dose [65,66]. In addition, subjective. The aim of the chronotherapeutic strategy is to ensure that
the absorption phase of NSAIDs in the morning was greater and faster patients receive maximum analgesia with minimal side effects. The
than in the evening [67,68]. The time of dosing with optimal effec- limited number of studies on this topic, the existence of circadian vari-
tiveness differed among subjects, maybe due to large interindividual ations in the intensity of pain, and the interindividual differences, do
differences in the circadian variation of self-rated pain intensity. Eve- not provide definite conclusions and suggest for tailored schedules.
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. 2.5. Drugs for acid-related disorders
Kowanko et al. [57] in a study on patients with rheumatoid arthritis
(RA), showed that a dose of 100 mg of flurbiprofen administered The gastrointestinal tract works following a biologic rhythm re-
twice daily was more effective than a dose of 50 mg ingested four garding basal gastric acid output, epithelial cell proliferation, gastro-
times daily. However, subjective measures of pain and stiffness indi- intestinal motility, and appetite regulation. The circadian pattern of
cated that one of the two doses of drug had to be taken during the gastric pH is characterized by a peak during early evening (6 p.m.–
night, in order to control effectively the morning stiffness and pain. 10 p.m.), and a progressive reduction during the night [78], even
As for adverse effects, they could be higher when the drugs were though significant differences in pH pattern may occur in healthy
ingested in the morning. Moore et al. [69], in fact, observed that the controls and patients with duodenal ulcer patients. A particular entity
number of gastric lesions produced by oral administration of 1 g of has been described as “nocturnal acid breakthrough”, defined as gas-
ASA at 10 a.m. was twice that the number of lesions produced by tric pH lower than 4 lasting for at least 60 consecutive minutes in the
oral administration of the same dose at 10 p.m. overnight period (10 p.m. to 6 a.m.) [79].

2.4.4. Corticosteroids 2.5.1. H2-receptor antagonists


As reported before, patients with rheumatoid arthritis usually in- Ranitine, given during night-time, was associated with a higher
dicate the presence of greatest pain in the morning [57]. Thus, a inhibition of intragastric acidity either in healthy subjects [80], and
new modified-release delivery system adapting the release of the ad- in patients with duodenal ulcer with nocturnal acid breakthrough
ministered glucocorticoid to the circadian rhythms of endogenous [81].
cortisol and disease symptoms, has been developed. A multicenter,
randomized, double-blind trial, was conducted in patients with active 2.5.2. Proton pump inhibitors (PPI)
rheumatoid arthritis, who were assigned to either a modified-release Plasma levels of lansoprazole were higher after morning dose [82],
prednisone tablet (taken at bedtime) or to an immediate-release and morning doses were associated with a higher effect on gastric pH
prednisone tablet (morning administration) [70]. Bedtime adminis- than evening doses [83]. Similar results were found for omeprazole
tration of modified-release prednisone was well tolerated, convenient [84] and pantoprazole [85]. There are no significant changes in the
to administer, and produced a clinically relevant reduction of morn- gastric pH levels according to time-dependent administration of
ing stiffness of the joints (− 22%). Of course, it has to be stressed tenatoprazole, although morning doses were associated with higher
that the circadian rhythm of corticosteroids has been established drug plasma concentrations [86]. In this respect, it should be noted
many decades ago. Thus, corticosteroids should be administered in that higher plasma levels of a drug do not necessarily correspond to
the morning, in the respect of such circadian rhythm, and the evening synchronous higher therapeutic effects. Keeping in mind that gastric
dosing schedule (of a slow released formulation) should be limited to pH is always much lower at night (the longest period of the day
arthritic patients. when no food is ingested, leaving gastric acidity unbuffered), what
really counts on a clinical basis is the net effect on nocturnal pH in-
2.4.5. Opioids duced by the different temporal administrations of antiacid drugs.
Morning seems to be the temporal window where opioids are most
required, at least in conditions of post-surgery intervention [71]. In fact, Take-home messages
self-administration of morphine was near 50% higher during the day
than during night [72]. Again, in patients with cancer pain, the distribu- A time-dependent efficacy of different drugs has been shown in sever-
tion of extra-doses of narcotic analgesics was 60% lower during the al studies, and a practical suggestion could be to use PPIs in the morn-
night than during the day [73], suggesting that the circadian distribu- ing and H2 receptor antagonists in the evening.
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 2.6. Bronchial asthma
in a study dealing with opioid overdose [74]. It has been stressed, how-
ever, that an intra-individual variation of in morphine absorption, pro- Chronobiological patterns of allergic rhinitis (AR) and bronchial
duction of the active metabolite morphine-6-glucuronide, and the 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 3. Conclusions


the remaining part of the day, and exacerbations of asthma being
more frequent during the night. The well known nocturnal parasym- In clinical practice, time of drug administration often matters, i.e. it
pathetic activity with consequent reduced bronchial caliber and is bound to affect the efficacy and side effects of many medications. In
raised airway resistance, the greater amount of inflammatory cell, this respect, some drug classes have been extensively studied (like
together with a lower function of neuroendocrine (hypothalamic– ACE-inhibitors, ARBS, alpha- and beta-blockers in hypertension, corti-
pituitary–adrenocortical) system, are all important factors responsi- costeroids and beta2-adrenergic agonists in asthma, simvastatin,
ble of the higher incidence of asthma during the night, including drugs for acid-related disorders), others have been studied with in-
early morning hours. complete or contrasting results (pain killers and anticoagulants),
many more still remain to be investigated. As summarized above, for
2.6.1. Corticosteroids some molecules we have clear indications that the most favorable
A pioneeristic study evaluating the relationship between cortico- time of administration is either the morning or the evening (very sel-
steroid therapy and time of administration [88] found that a dose dom, studies are available comparing other times of administration).
of methyl-prednisolone (40 mg) was more effective on peak Moreover, some evidence indicates the possibility that a preferred
expiratory flow rate (PEFR) when administrated at 3 p.m., and less time of administration is molecule specific in some cases, and
effective at 3 a.m. and 7 p.m. The authors reported a reduction of class-specific in others. In any case, the applicability of such aspects
biomarkers of inflammation, evaluated by blood eosinophil and to clinical practice is often limited also by individual factors, such as
pancellular bronchoalveolar lavage cytology. Further confirmations normal synchronization or desynchronization of the individual CTS,
came from Beam et al. [89], who treated patients with oral dose of induced by different lifestyles or even by disease itself, like it often
prednisone at 8 a.m., 3 p.m. and 8 p.m., obtaining an increase of happens in cancer patients. Altogether, the above characteristics ap-
FEV1 and decreasing inflammation (compared to placebo) in the pear to limit the generalization of a temporal prescription of many
group receiving the drug at 3 p.m. Again, Pincus et al. [90] showed drugs. Again, we do not know enough about the effect or interactions
that a single dose of corticosteroid administered at 3 p.m. was more of polypharmacy, and, especially in elderly patients assuming multiple
effective in improving FEV1 than the 4 doses of 200 μg. As for medications, whether the most appropriate “circadian” administra-
inhaled corticosteroids, no significant differences were found among tion could be in tune (or be against) the risk of pharmacological inter-
3 treatments: 500 μg of inhaled beclomethasone twice-daily, or actions. While we have to wait for prospective intervention trials
1000 μg in the late afternoon or 1000 μg at bedtime [91]. Similar re- specifically designed to investigate the long-term effects of such
sults were found with mometasone furoate [92] and budesonide [93]. a temporal approach to therapy in many diseases, although some
recent studies provided convincing preliminary evidence that a
2.6.2. Beta2-adrenergic agonists chronotherapeutic approach with antihypertensive medications is as-
A study on patients with poorly controlled nocturnal asthma, sociated with a significant reduction of cardiovascular events [33,34],
showed that a single dose of salmeterol 100 μg given in the evening we already have reasons to compare in our individual patients the dif-
had the same effect compared with two daily doses of 50 μg, even if ferences in efficacy and side effects often documentable between
evening administration was associated with higher FEV1 [94]. Similar morning and evening administration. Since such switch represents
results on bronchodilation were obtained with different types of simple and inexpensive procedure, which in turn may result in dra-
beta2-adrenergic agonist drugs (formoterol 24 μg, 50 μg salmeterol matic improvements or worsenings in efficacy and/or adherence to
and salbutamol 200 μg) [95]. The evening dose of combined cortico- therapy, we believe that this is a promising field which deserves fur-
steroids and beta2-adrenergic agonists was better than the morning ther investigation aimed to obtain precious indications on how to op-
dose in improving FEV1 and maximum expiratory flow at 25–75% of timize the temporal aspects of drug administration. In any way,
forced vital capacity (MEF25–75%) [96]. accurate adherence to pharmacological schedules is the crucial point
for the clinical success of a therapy, and it should be always pursued.
2.6.3. Anticholinergics
Although cholinergic tone is increased during the night, a double
Learning points
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 • Chronobiology is a branch of biomedical sciences devoted to the
(9 p.m.), or an identical placebo doses, showed that there were no study of biological rhythms, and circadian rhythms are the most
significant differences in the morning versus evening administration commonly and widely studied.
[97]. • According to body rhythms, it is possible that a given medication
may be therapeutic and safe when administered at some biological
2.6.4. Leukotriene receptor antagonists time, but subtherapeutic or poorly tolerated at another time.
Cysteinyl leukotrienes are derivatives of arachidonic acid metabo- • In clinical practice, time of drug administration often matters, i.e. it
lism, and are important mediators of airway inflammation. Among is bound to affect the efficacy and side effects of many medications.
these, montelukast is one of the most widely used leukotriene recep- • Some evidence indicates the possibility that a preferred time of ad-
tor antagonists. Although a first study reported a higher effectiveness ministration is molecule specific in some cases, and class-specific in
after evening administration [98], another study [99] failed to find others. ACE-inhibitors or angiotensin receptor blockers, simvastat-
significant differences in its effect depending on morning versus eve- in, corticosteroids (slow-release formulation) for arthritic patients,
ning administration. and ranitidine should preferably be administered in the evening.
Morning dosing could be better for proton pump inhibitors, where-
Take-home messages as time of administration of inhalation medications for asthma is
not crucial.
Although, in line of principle, bronchodilators are preferred for diur- • Studies are available also for other drugs, but the evidence is not
nal dosing and anti-parasympathetic drugs for evening dosing, no strong enough to draw definite conclusions. Prospective interven-
definite conclusions can be drawn from the available evidence. In tion trials specifically designed to investigate the long-term effects
particular, in the case of drugs administrated by inhalation, their of such a temporal approach to therapy in many diseases are
effects appear to be independent of time of administration. needed.
A. De Giorgi et al. / European Journal of Internal Medicine 24 (2013) 698–706 705

Conflict of interests administration of torasemide in essential hypertension. Chronobiol Int 2008;25:


950–70.
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None of the authors have any actual or potential conflict of inter- morning and evening dosing of nebivolol reduces trough mean blood pressure
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