Table 3.

Clinical trials and studies considering time of day in the treatment of disorders involving the immune system.

DRUG CLASS	DRUG(S)	STUDY DESIGN; POPULATION	STUDY CONCLUSIONS	SUGGESTED TIME OF DAY	CITATION
Rheumatoid Arthritis
Glucocorticoids	Prednisolone	41 patients	Bedtime dose (between 2200 −2300 h) significantly reduced morning stiffness as compared to morning (0700 h) dose.	Bedtime (between 2200 −2300 h)	De Silva, Binder et al. 1984
		85 women	Mean pain score based from the disease activity score 28, duration of morning stiffness, and erythrocyte sedimentation rate were decreased when administered at (2200 h) compared to (0800 h)	Night (2200 h)	Gul H 2017
	Prednisone Modified Release (PMR) v. Prednisone Rapid Release (PRR)	288 patients	PMR significantly reduced morning pain intensity and duration, DAS28, and plasma IL-6 levels, compared to PRR in the morning.	Evening	Buttgereit, Doering et al. 2008, Buttgereit, Doering et al. 2010
DMARDS	Methotrexate	Prospective, single-arm study; 17 patients	Methotrexate dosing from morning to bedtime led to significant improvements in both DAS28 and modified health questionnaire (MHAQ) scores in a cohort of RA patients	Bedtime, 3x/wk	To, Yoshimatsu et al. 2011
Osteoarthritis
NSAIDs (Aspirin)	Flurbiprofen	Double-blind crossover study; 17 patients	Twice-daily dosing regimens that included an evening dose were more effective in reducing RA symptoms and increasing grip strength.	2x/daily with an evening dose	Kowanko, Pownall et al. 1981
	Indomethacin	Double-blind crossover study in 66 patients with osteoarthritis	Evening administration (2000 h) reduced morning pain and reported the fewest undesirable effects and that worsening afternoon or evening pain was best relieved by administration in morning (0800 h) or afternoon (1200 h).	Evening	Levi, Le Louarn et al. 1985
	Ketoprofen	double-blind randomized trial in 117 osteoarthritis patients	Evening dosing (2000 h) caused longer duration of analgesia with fewer adverse effects when compared to morning dosing (0800 h).	Evening	Perpoint, Mismetti et al. 1994
Multiple Sclerosis
Cytokines	IFN-β1	16 patients with relapsing/remitting MS	On day 1 of treatment, morning injection resulted in higher plasma IL-10; evening injection caused an earlier and more robust peak in cortisol, increased soluble tumor necrosis factor receptor 1 & 2 (sTNF-R), and increased plasma IL-1, which was associated with more intense negative side effects; after 6 months of IFN-β therapy, elevated sTNF-R1 in the morning group was the only difference reported.	Inconclusive	Kumpfel, Schwan et al. 2007
	IFN-β	105 patients	Switching from evening to morning injections of IFN-β qualitatively improved flu-like symptoms (58%) and sleep quality (48%), common side effects from INF-β delivery	Morning	Nadjar, Coutelas et al. 2011
	IFN-β1a	Randomized controlled parallel-group trial in 200 patients with relapsing MS	Morning administration reported more intense flu-like symptoms at weeks 4 & 8; by week 12 there were no differences in symptoms between groups. No reported effects of time-of-day on dosing, sleep quality, fatigue severity, or circulating leptin, resistin, and adiponectin after 12 weeks of therapy.	No differences	Patti, Zimatore et al. 2020
Glucocorticoid	Methylprednisolone	17 patients	Night (2200 – 0200 h) administration vs. day (1000 – 1400 h) was reported to reduce serum MMP-9 and adverse events, including symptoms such as insomnia, depression, headaches, restlessness, gastrointestinal symptoms, palpitations	Night (2200 – 0200 h)	Glass-Marmor, Paperna et al. 2007
Asthma treatments
Glucocorticoids	Triamcinolone	30 patients	Equally effective when administered as a single 800 μg dose at 1500 h when compared to 200 μg 4x/day. Authors suggest 1x/d dose should increase compliance of steroid use,	1x/d at 1730 h or 4x/d	Pincus, Szefler et al. 1995
		59 subjects	Equally effective administered as a single dose at 1730 h or 4x/d, but a single dose at 0800 h was less beneficial in comparison to the other dosing regimens.	Afternoon (1500 −1730 h)	Pincus, Humeston et al. 1997
	Mometasone Furoate	Open-label, randomized, parallel-group study; 1537 subjects with mild to moderate asthma	No difference between morning or evening administration on subjective symptoms.	No difference	Zetterstrom, Dahl et al. 2008
	Fluticasone Fluroate	Randomized double-blind clinical trial; 28 patients	No difference between morning or evening administration on subjective symptoms.	No difference	Kempsford, Bal et al. 2016
Glucocorticoids + β-agonist	Fluticasone Furoate + β-agonist Vilanterol	Randomized, double-blind crossover clinical trial; 26 subjects	No difference between morning or evening administration on subjective symptoms.	No difference	Kempsford, Oliver et al. 2013
	Bambuterol	Double-blind, randomized, placebo-controlled, crossover study; 29 patients	Reduced symptoms at either 0700 h or 2200 h; evening administration produced the most improvement in morning forced expiratory volume.	Evening	D’Alonzo, Smolensky et al. 1995
Nonselective phosphodisterase enzyme inhibitor	Sustained release theophylline	25 adult patients	Once (2000 h) or twice (0800 & 2000 h) daily doses had similar improvement in airflow. Single evening dose significantly improved peak expiratory flow rate and forced expiratory volume between 0200 h and 0600 h.	Similar improvements; evening dose had additional benefits.	D’Alonzo, Smolensky et al. 1990
	Extended release theophilline	Double-blind crossover study; 8 pediatric patients	Treatment irrespective of dosing time resulted in comparable enhancement of the group24-hr mean, minimum and maximum values of airways patency with reference to placebo baselines. However, dosing at 1500 or 2100 h, resulted in the best effect on the airways as assessed by the 24-hr mean forced expiratory volume.	Evening (1500 h) or Night (2100 h)	Smolensky, Scott et al. 1987
Allergic Rhinitis
H1 Histamine Antagonist	Mequitazine	Multicenter	Dinner-time dosing was more effective at controlling morning peak and 24-h symptoms, as compared to breakfast dosing.	Dinner-time	Reinberg, Gervais et al. 1985
	Desloratadine	randomized study in 663 adult AR patients	No difference in morning vs evening administration.	No difference	Haye, Hoye et al. 2005
	Cetirizine	two multicenter, randomized, double-blind, parallel-group studies	Morning and evening administration was equally effective at symptom relief in seasonal AR.	No difference	Urdaneta, Patel et al. 2018
Nasal Decongestants	Pseudoephedrine	Randomized, double-blind, crossover study in 9 male athletes	Morning (0700 h) but not afternoon (1700 h) supra-therapeutic dose boosted muscle contraction velocity in squat exercises.	Morning (0700 h)	Pallares, Lopez-Samanes et al. 2015
Cystic Fibrosis
Antibiotic	Tobramycin	Randomized trial in 18 children	Morning (0800 h) compared to evening (2000 h) administration showed no differences in pharmokinetics due to time of day, however urinary KIM-1 (kidney injury molecule) was higher in the 2000 h group, indicating greater potential for kidney damage with evening dosing	Morning due to evening side effects	Prayle, Jain et al. 2016
		25 adult CF patients	No differences in pharmacokinetics due to time of day, but the evening group (2200 h) had increased serum blood urea nitrogen compared to the morning (0800 h) group	Morning due to evening side effects	van Maarseveen, van der Meer et al. 2020
Eczema / Psoriasis
Corticosteroids	Betamethasone		Maximal therapeutic effects achieved on healthy skin with a late afternoon application.	Late afternoon	Pershing, Corlett et al. 1994
			Evening application was more effective than morning application; however, its effects were attenuated after 5 nights of application.	Evening	Nguyen, Lacour et al. 2017
Vaccines
Vaccines	Influenza and Hepatitis A		Morning vaccinations produce enhanced antibody responses compared to those given in the afternoon.	Morning	Phillips, Gallagher et al. 2008, Kirby 2016, Long, Drayson et al. 2016