 |
|
Akathisia With Combined Use of Midodrine and Promethazine
To the Editor: Midodrine is commonly prescribed for treatment of orthostatic hypotension.1 We have been studying its use as a pharmacological countermeasure for post-spaceflight orthostatic hypotension because it is fast acting and has no known cardiac or central adverse effects.1 Promethazine is the antiemetic of choice by National Aeronautics and Space Administration (NASA) flight surgeons for the treatment of postflight nausea and vomiting. Because midodrine and promethazine would likely be used together on landing day, we studied whether promethazine would counteract the positive effects of midodrine on orthostatic tolerance. In the course of that study, we observed an unexpected degree of akathisia.
Methods
Ten healthy participants were recruited from the general public by the Johnson Space Center Test Subject Facility. One withdrew from the study before testing. The remaining participants received all 4 possible sequences of treatment in random order, separated by at least 4 days. Treatment consisted of either midodrine, 10 mg oral, or placebo, followed 60 minutes later by either promethazine, 25 mg intravenously infused over 12 minutes, or placebo. Placebos were identical in appearance, taste, and smell to the corresponding test drugs. Midodrine or oral placebo was given first to duplicate a post-spaceflight regimen. No participant consumed any other medication within 24 hours before testing.
Akathisia severity was quantified with the 0 to 5 Barnes global akathisia score: 0, no akathisia; 1, nonspecific inner tension and fidgety movements; 2, awareness of restlessness, primarily in the legs, that is worse when required to stay still; 3, symptoms of a score of 2 plus rocking movements and distress; 4, compulsive desire to move, with distress; 5, inability to remain still, with distress, insomnia, and severe anxiety.2 Data were normally distributed and had equal variance. Treatments were compared using repeated measures analysis of variance with a Bonferroni multiple comparison posthoc test. Analyses were performed using SigmaStat version 3.1 (Systat Software Inc, Richmond, Calif). Significance was set at P .05.
All participants gave written informed consent to participate in this protocol, which was approved by the Johnson Space Center Committee for the Protection of Human Subjects, and received a small stipend.
Results
Akathisia was experienced by no participant treated with both placebos, no participant with midodrine alone, 4 participants with promethazine alone, and 6 participants with midodrine and promethazine together (Table). Participants who scored 3 or 4 also reported feelings of claustrophobia. The severity of akathisia by Barnes score was significantly greater with midodrine and promethazine together (mean [SE] 2.0 [0.6]) than with promethazine alone (0.8 [0.4], P = .047), midodrine alone (0.0 [0.0], P<.001), or placebo (0.0 [0.0], P<.001).
|
|
|
|
Table. Responses to Promethazine Alone and Promethazine Plus Midodrine
|
|
|
Comment
The severity of akathisia that occurred during the use of promethazine and midodrine together in a majority of our participants was unexpected. While it is known that phenothiazines (including promethazine) can induce akathisia,3 we are not aware of any reports that midodrine promotes this reaction.
Both drugs are metabolized by the cytochrome P450 isozyme CYP2D6.4-5 Promethazine given in the presence of midodrine may therefore have increased bioavailability and decreased clearance. Because of the highly polymorphic nature of this enzyme in the population, poorer metabolizers may be more susceptible to this kinetic interaction.4
While these findings must be considered preliminary due to the small number of participants and posthoc nature of the hypothesis, NASA has prohibited the use of the 2 drugs together. The adverse effects have the potential for risk in persons driving or performing other hazardous activities. Since its approval by the US Food and Drug Administration, midodrine has become a first-line treatment for patients with orthostatic hypotension.1, 6 Physicians prescribing either drug should be aware of this potential drug interaction and should specifically be aware of any midodrine use before prescribing promethazine or drugs metabolized by CYP2D6.
Author Contributions: Dr Meck had full access to all of the data and takes responsibility for the integrity and accuracy of the data analysis.
Study concept and design: Shi, Meck.
Acquisition of data: Platts, Shi, Meck.
Analysis and interpretation of data: Platts, Shi, Meck.
Drafting of the manuscript: Platts, Meck.
Critical revision of the manuscript: Platts, Shi, Meck.
Statistical analysis: Platts.
Obtained funding: Meck.
Administrative, technical, or material support: Platts, Shi, Meck.
Study supervision: Platts, Meck.
Financial Disclosures: None reported.
Funding/Support: This work was supported by NASA grant NAS9-97005 to Dr Meck.
Role of the Sponsor: The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Steven H. Platts, PhD
Universities Space Research Association
Shang-Jin Shi, MD, PhD
Wyle Laboratories
Janice V. Meck, PhD
jmeck{at}ems.jsc.nasa.gov
Human Adaptation and Countermeasures Office
NASA Johnson Space Center
Houston, Tex
1. McTavish D, Goa KL. Midodrine. A review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders. Drugs. 1989;38:757-777.
ISI
| PUBMED
2. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676.
FREE FULL TEXT
3. Dundee JW, Moore J, Love WJ, Nicholl RM, Clarke RS. Studies of drugs given before anaesthesia: VI, the phenothiazine derivatives. Br J Anaesth. 1965;37:332-353.
FREE FULL TEXT
4. Nakamura K, Yokoi T, Inoue K, et al. CYP2D6 is the principal cytochrome P450 responsible for metabolism of the histamine H1 antagonist promethazine in human liver microsomes. Pharmacogenetics. 1996;6:449-457.
PUBMED
5. Akimoto M, Iida I, Itoga H, Miyata A, Kawahara S, Kohno Y. The in vitro metabolism of desglymidodrine, an active metabolite of prodrug midodrine by human liver microsomes. Eur J Drug Metab Pharmacokinet. 2004;29:179-186.
PUBMED
6. Kochar MS. Management of postural hypotension. Curr Hypertens Rep. 2000;2:457-462.
PUBMED
Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2006;295:2000-2001.
|
