Timing the Tab-late

Thyroid_goitre_-_massive

The conventional wisdom states that the intake of thyroid hormone replacement is best when done in the morning, on an empty stomach, in order to allow the best absorption and a more predictable range of serum concentration, thereby preventing potentially iatrogenic hypothyroidism. Now, this has also been studied, albeit in small groups (1), showing that Nonfasting regimens of levothyroxine administration are associated with higher and more variable serum TSH concentrations. If a specific serum TSH goal is desired, thereby avoiding iatrogenic subclinical thyroid disease, then fasting ingestion of levothyroxine ensures that TSH concentrations remain within the narrowest target range.

There has been little to no hard evidence challenging this fact, and it came to me quite as a surprise when I stumbled across a study (2) which advocates the intake of thyroxine at bedtime. The investigators performed a randomized, double-blind, crossover trial on 105 consecutive patients of primary hypothyroidism. Patients were instructed during 6 months to take 1 capsule in the morning and 1 capsule at bedtime (one containing levothyroxine and the other a placebo), with a switch after 3 months. Primary outcome measures were thyroid hormone levels; secondary outcome measures were creatinine and lipid levels, body mass index, heart rate, and quality of life. They found that:

Compared with morning intake, direct treatment effects when levothyroxine was taken at bedtime were a decrease in thyrotropin level of 1.25 mIU/L (95% confidence interval [CI], 0.60-1.89 mIU/L; P < .001), an increase in free thyroxine level of 0.07 ng/dL (0.02-0.13 ng/dL; P = .01), and an increase in total triiodothyronine level of 6.5 ng/dL (0.9-12.1 ng/dL; P = .02). Secondary outcomes, including quality-of-life questionnaires (36-Item Short Form Health Survey, Hospital Anxiety and Depression Scale, 20-Item Multidimensional Fatigue Inventory, and a symptoms questionnaire), showed no significant changes between morning vs bedtime intake of levothyroxine.

What it effectively means that with bedtime ingestion of the drug, there is better treatment of primary hypothyroidism, although there seem to be no quality of life issues in either case (as would be expected of a drug with a once-a-day regime). Notably, in the previous study, looking at the timing of the Levothyroxine administration (1), the end point of assessment was serum TSH and not thyroid hormones, although in the present study, even those levels seem to have gone down.

The study is remarkable from the viewpoint that it has stood up and challenged a long standing, universally accepted dosing strategy, and has found it to be not so fool proof as one would ass+u+me. However, I am not so sure whether I will be advising a change in dosing strategy for my patients right away.

There are several reasons for the same. For one thing, the study involves a population ethnically, and hence, genetically very diverse from the one I cater to. Also, I would prefer bigger numbers before I definitely go ahead and put myself on the line. I believe generating locally viable information would not be too challenging since it would be an easy study to conduct, essentially, since there is no dearth of patients of this particular problem in my setting. However, until more studies validate this finding, I am not going to go ahead and advocate the change. Mainly because this I view as a form of defensive practice. the methodology looks simple and elegant, and there seem to be no statistical glitches that I can spot either. So, theoretically, it appears pretty neat to me (me being the operational word here!).

However, one issue with all bed time drugs is compliance. Many of the patients of primary hypothyroidism that I have seen and treated are shift workers, or have very heavy evening working schedules and it is quite possible that they would miss the drug at bed time rather than take it first thing in the morning. How many nights have I myself had a pizza for dinner on the way home from the hospital and crumpled down on my bed in a heap, finally thankful to be asleep? And the risk is high especially with the trend of more and more adults of the 30-45 year age range getting treatment for this condition.

Another cultural thing is how dinner and bedtime follow each other with almost no time in between in my practice setting. Given the fact that thyroxine absorption is aberrant on a full stomach, this could also be a potentially worrying factor.

These are the reasons for which I will still advice my patients to take the pill first thing in the morning, but, at the same time, will provide them with the new information which is getting out (just to show off that I am keeping up with the newer things around!). But I will wait for more local results, more relevant evidence, more compelling numbers before I actively advocate a bedtime ingestion of thyroxine.

Note to self: Good research question: for later, when I have some time, and have solved the eternal PGMEE puzzle!

References:

1. Thien-Giang Bach-Huynh, Bindu Nayak, Jennifer Loh, Steven Soldin, and Jacqueline Jonklaas. Timing of Levothyroxine administration Affects Serum Thyrotropin Concentration J. Clin. Endocrinol. Metab. 94: 3905-3912; published online before print as doi:10.1210/jc.2009-0860

2. Nienke Bolk; Theo J. Visser; Judy Nijman; Ineke J. Jongste, RN; Jan G. P. Tijssen; Arie Berghout Effects of Evening vs Morning Levothyroxine Intake: A Randomized Double-blind Crossover Trial Arch Intern Med. 2010;170(22):1996-2003
ResearchBlogging.org

Study in Focus:

Bolk, N., Visser, T., Nijman, J., Jongste, RN, I., Tijssen, J., & Berghout, A. (2010). Effects of Evening vs Morning Levothyroxine Intake: A Randomized Double-blind Crossover Trial Archives of Internal Medicine, 170 (22), 1996-2003 DOI: 10.1001/archinternmed.2010.436

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