The impact of pseudoephedrine and antihistamine on lower urinary tract symptoms in male patients with rhinitis: A prospective randomized study

Chen-Che Lee; Yuan-Yun Tam; Ying-Hsu Chang; Ming-Li Hsieh; I-Hung Shao

doi:10.4103/UROS.UROS_85_19

ORIGINAL ARTICLE

Year : 2020 | Volume : 31 | Issue : 3 | Page : 108-113

The impact of pseudoephedrine and antihistamine on lower urinary tract symptoms in male patients with rhinitis: A prospective randomized study

Chen-Che Lee¹, Yuan-Yun Tam², Ying-Hsu Chang¹, Ming-Li Hsieh¹, I-Hung Shao¹
¹ Division of Urology, Department of Surgery, Linkou Chang Gung Memorial Hospital; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
² Department of Otolaryngology, Head and Neck Surgery, Tao Yuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan

Date of Submission	04-Nov-2019
Date of Decision	05-Mar-2020
Date of Acceptance	08-Mar-2020
Date of Web Publication	26-Jun-2020

Correspondence Address:
I-Hung Shao
Division of Urology, Department of Surgery, Linkou Chang Gung Memorial Hospital, No. 5 Fu-Shing Street, Kweishan, Taoyuan 333
Taiwan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/UROS.UROS_85_19

Abstract

Purpose: The effects of medications for treating nasal congestion on voiding function remain unclear. In this study, we aimed to elucidate the effects of the common decongestants, pseudoephedrine, and antihistamine, on voiding dysfunction in men without clinical lower urinary tract symptoms. Materials and Methods: We prospectively enrolled 200 consecutive male patients who visited the otolaryngology department for rhinitis from August 2015 to August 2016. These patients were then randomized to the pseudoephedrine or antihistamine groups. The International Prostate Symptom Score (IPSS) and postvoiding residual urine (PVR) were assessed before and 1 week after treatment and the results were analyzed. Patients were further stratified by age (≥50 years old vs. <50 years old) and IPSS (>7 vs. ≤7) in each group and comparison analyses were conducted. Results: There were no significant differences between the baseline characteristics of the pseudoephedrine and antihistamine groups. The IPSS total, IPSS voiding, and IPSS storage (IPSS-T, IPSS-V, and IPSS-S, respectively) tended to increase in the pseudoephedrine group but did not reach statistical significance. Similar results regarding IPSS-T and IPSS-V were seen in the antihistamine group. The IPSS-T increased significantly in patients ≥50 years old treated with pseudoephedrine, which was not observed in the antihistamine group. The IPSS-V was significantly higher in patients <50 years old treated with antihistamine. The PVR did not significantly change after treatment with both drugs. However, in patients with baseline IPSS-T >7 treated with pseudoephedrine, the PVR tended to increase. Conclusion: Pseudoephedrine and antihistamine have minimal effects on lower urinary tract function in the general male population. However, pseudoephedrine worsened IPSS-T in elderly men, whereas antihistamines worsened IPSS-V in younger men. In self-unaware voiding dysfunction male with IPSS-T > 7, pseudoephedrine may cause more PVR. Thus, in elderly men with rhinitis, antihistamines may be more suitable, while pseudoephedrine would be preferable in younger men.

Keywords: Antihistamine, decongestant, International Prostate Symptom Score, nasal congestion, pseudoephedrine, voiding dysfunction

How to cite this article:
Lee CC, Tam YY, Chang YH, Hsieh ML, Shao IH. The impact of pseudoephedrine and antihistamine on lower urinary tract symptoms in male patients with rhinitis: A prospective randomized study. Urol Sci 2020;31:108-13

How to cite this URL:
Lee CC, Tam YY, Chang YH, Hsieh ML, Shao IH. The impact of pseudoephedrine and antihistamine on lower urinary tract symptoms in male patients with rhinitis: A prospective randomized study. Urol Sci [serial online] 2020 [cited 2023 May 28];31:108-13. Available from: https://www.e-urol-sci.com/text.asp?2020/31/3/108/287982

Introduction

Patients suffering from voiding dysfunctions after being treated for nasal congestions were occasionally seen in the emergency room (ER) or being referred from otorhinolaryngology outpatient department (OPD). Pseudoephedrine and antihistamines are two commonly used nasal decongestants, both of which work in different ways. Pseudoephedrine is a sympathomimetic amine that acts on the adrenergic receptor system of α and β2. By affecting α-receptors, it causes smooth muscle in the blood vessels to contract, leading to vasoconstriction in the nose, throat, and sinus lining, thus decreasing nasal congestion and mucous production. However, the same α-adrenergic receptor action results in adverse effects on male urinary retention by causing smooth muscle contraction in the bladder neck, urethra, and prostate.^[1] The β2 action, while relaxing the smooth muscle of the bronchi resulting in dilation and decrease of congestion, also relaxes the smooth muscle of the bladder, leading to more difficult voiding.^[1],[2]

Antihistamines are differentiated based on the receptors they act upon. H1 antihistamines work against H1 receptors, which are mostly present in smooth muscles of airways, cardiovascular system, endothelial cells, and lymphocytes. The antagonist action on H1 histamine receptors decreases inflammatory processes by attenuating NF-κB expression, in turn suppressing the swelling and vasodilatation of cells, which relieves the allergic and mast cell-related response. The mechanism through which the drug causes urinary retention is not well known; however, it is believed to be related to the anticholinergic effects caused when binding to muscarinic receptors as well as the sedation effect when the drug crosses the blood-brain barrier.^[1],[3]

Patients with acute urine retention (AUR) or lower urinary tract symptoms usually consult the urology OPD or the ER. According to two large studies, the overall incidences of men with AUR in the US were 4.5/1000 person-years and 6.8/1000 person-years.^[4],[5] Most of these patients present with benign prostate hypertrophy (BPH) as it is one of the major risk factors. However, few studies have focused on asymptomatic patients, those who did not know they had BPH.

The use of calcium channel antagonists and anticholinergic drugs, according to Meigs et al., can double and triple the incidence of AUR in men >45 years old.^[4] Both pseudoephedrine and antihistamine are known to affect the male urinary tract; therefore, caution is advised when administering these to patients with BPH, but no further precautions regarding patient age have been noted.^[6] In our previous study, we pointed out that older age and higher premedication International Prostate Symptom Score-voiding (IPSS-V) significantly worsen voiding dysfunction. In patients ≥50 years old, the IPSS significantly increases, but the quality of life (QoL) does not significantly decrease.^[7] However, no subjective measurements were used in that study. To the best of our knowledge, there is no study that compares the effects of pseudoephedrine and antihistamine on men without known BPH using subjective measurements such as postvoiding residual (PVR).

Subjects and Methods

Participants

This is a prospective study approved by the Linkou Chang Gung Memorial Hospital institutional review board (IRB No. 104-2819B). From August 2015 to August 2016, consecutive male patients with acute or chronic rhinitis who visited the otolaryngology OPD were enrolled in our study. This study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients. The inclusion criteria were as follows: (1) male of 18 years old or older; (2) having complaints of acute or chronic rhinitis which needed medication treatment; (3) without the known self-claimed or medical history of complicating diseases; (4) being capable of completing the questionnaire and further bladder scan study.

The exclusion criteria included the following: (1) men who claimed to have previous medical or surgical records of BPH; (2) having complaints of lower urinary tract symptoms whether under medication or not; (3) those in whom the use of pseudoephedrine and antihistamine was contraindicated; (4) currently using pseudoephedrine and/or antihistamine; (5) those who failed to finish the full course of medication or to complete the questionnaire and bladder scan.

A total of 200 men were enrolled and randomized to pseudoephedrine and antihistamine groups by their medical record numbers. In the pseudoephedrine group, pseudoephedrine sulfate 120 mg BID was used with plasma peak concentration at 7.22 h and half-life of 6.48 h.^[8] Desloratadine 5 mg QD with a plasma peak concentration at 3.98 h and half-life of 26.8 h was used in the antihistamine group.^[9] According to the pharmacokinetic profile of both drugs and the practice of our OPD, a week of medication treatment was given before further follow-up.

Patients were required to complete the IPSS questionnaire before and 1 week after receiving medications. PVR urine was also measured before and 1 week after treatment in the OPD with the bladder scan by the doctor.

Patients in each group were divided into subgroups by age (≥50 years old vs. <50 years old) and initial IPSS (>7 vs. ≤7) for further comparison.

Measurement of lower urinary tract symptoms and postvoiding residual urine

The IPSS (Hong Kong Chinese version 2) was used to evaluate voiding dysfunction. The IPSS questionnaire, first introduced in 1992, is now used by urologists worldwide to evaluate voiding dysfunction.^[10] It contains two parts as follows: The IPSS-V and the IPSS storage (IPSS-S). There are a total of seven questions, each scoring from 0 to 5 points, leading to a maximum score of 35 points. An eighth question, which measures the QoL-US on a scale from 0 to 6, was added in 1993 by the World Health Organization.^[11] The results were analyzed based on the IPSS total (IPSS-T), IPSS-V, IPSS-S, and QoL-US. We used the Hong Kong Chinese version 2 IPSS, which is a valid and reliable tool for measuring lower urinary tract symptoms.^[12] We defined worsening voiding function as increasing scores after medication.

Patients were asked to lie on the bed after voiding with a probe placed one inch above the symphysis pubis for scanning and measurement of the residual urine amount using Verathon^® BladderScan BVI 9400 Portable Ultrasound.

Statistical analysis

Independent t-test was used for the continuous variables. Results between premedication and postmedication were compared using paired sample t-test in pseudoephedrine and antihistamine groups, as well as age-(≥50 and < 50 years old) and IPSS-(>7 and ≤ 7) stratified groups. Statistical analyses were performed using the Statistical package SPSS for the Windows (version 17.0) (SPSS Inc., Chicago, IL, USA), with a P < 0.05 considered statistically significant.

Results

A total of 200 men were divided into two groups: 100 receiving pseudoephedrine and 100 receiving antihistamine. All participants were adults and completed the questionnaire before and 1 week after medication. PVR was measured before and 1 week after medication. Patients' basic demographic data obtained from OPD are shown in [Table 1]. The mean age was 41.6 years and 41.4 years in the pseudoephedrine and antihistamine groups, respectively. The IPSS-T and IPSS-V increased after treatment in both groups, but not significantly. The IPSS-T increased from 6.48 to 6.92 in the pseudoephedrine group and from 6.28 to 6.47 in the antihistamine group. The IPSS-V increased from 3.27 to 3.59 in the pseudoephedrine group and 2.43–2.83 in the antihistamine group. The IPSS-S increased from 3.25 to 3.33 in the pseudoephedrine group but decreased from 3.85 to 3.76 in the antihistamine group; however, the differences were not statistically significant, as shown in [Table 2].

Table 1: Patients' baseline characteristics before medication

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Table 2: Premedication and postmedication comparison of International prostate symptom score scores and postvoiding residual urine in age-stratified patient groups

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To study the influence of age, both groups were divided into ≥50 or <50 years old. In men ≥50 years old, a significant increase in the IPSS-T was noted in the pseudoephedrine group (9.8–11.3, P = 0.018), while IPSS-V and IPSS-S increased. The differences were not significant [Table 2]. In the antihistamine group, decreases in the IPSS-T and IPSS-S were seen, while the IPSS-V increased; however, all changes were nonsignificant. In patients <50 years old, all scores increased nonsignificantly in the pseudoephedrine group. In the antihistamine group, the increases in IPSS-T and IPSS-S were also nonsignificant, but a significant increase was seen in the IPSS-V, from 1.79 to 2.40 (P = 0.014).

No significant increase of PVR after the medication was seen in both groups. We divided patients into IPSS-T ≤7 and >7 to determine whether mild or more severe premedication voiding dysfunction leads to a greater increase in PVR. No difference was seen in patients with IPSS-T ≤7 in both groups. A significant increase of PVR in IPSS >7 patients was noted in the pseudoephedrine group (premedication 38.4 ml to postmedication 45.5 ml, P = 0.02). Patients also reported a significant decrease in QoL in the same group, as shown in [Table 3]. [Figure 1] shows the change in the PVR before and after medication in both groups. No patients reported AUR or visited the ER throughout this study.

Table 3: Premedication and postmedication comparison of International Prostate Symptom Score scores and postvoiding residual urine in international prostate symptom score -stratified patient groups

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Figure 1: Changes in postvoiding residual urine after treatment with pseudoephedrine and antihistamine for nasal congestion stratified by age and international prostate symptom score scores. The specific postmedication postvoiding residual urine significantly increased in the psuedoephedrine group. *P < 0.05. IPSS: International prostate symptom score, PVR: Postvoiding residual urine

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Discussion

Due to the complexity of the process of micturition, many drugs may interfere with the pathway. Murray et al.^[13] studied 310 patients who were hospitalized due to AUR and determined that, in approximately 2% of the cases, the AUR could be attributed to concomitant medication use. Gatti et al.^[14] reviewed 53 children, who were admitted to two hospitals over 6 years due to AUR, and found that, in 13% of cases, the AUR was due to adverse drug effects. Kurasawa et al.^[15] studied 100 patients with chronic urine retention in a single institute and found that, in 12% of the cases, the condition was caused by medications, including drugs for the common cold.

Two well-known drugs used for rhinitis are pseudoephedrine and antihistamine. Pseudoephedrine is an adrenoceptor agonist that selectively affects the α- and β2-receptors. By binding to α1B-receptors on the vessel wall, it can decongest nasal mucosa, relieving rhinosinusitis. However, it may also bind to the α1A/D-receptors of the internal sphincter located at the proximal urethra, increasing muscle tone and causing voiding difficulties.^[16] The drug also acts on β-adrenoceptors. On the one hand, it relaxes the smooth muscles in the bronchi, causing dilation and decreasing congestions. On the other hand, it causes relaxation of the smooth muscle of the bladder wall. Therefore, in total, pseudoephedrine tends to maintain a continent bladder. Due to this effect, it is sometimes used to treat certain forms of incontinence.^[17] In a randomized, double-blind, double-dummy, placebo-controlled trial, Gelotte et al.^[18] showed that combined use of pseudoephedrine with ibuprofen significantly improved primary nocturnal enuresis in children. Since 1928, cases of voiding difficulty during pseudoephedrine use have been reported.^[19] Occasionally, patients need to visit the ER or urology OPD for treatment, but the urine retention is mostly temporary and manageable with catheterization and drug discontinuation. Thus, although contraindicated for patients with known urine retention, it is still used as a decongestant for patients without known voiding problems.

Histamine H1 receptor antagonists mediate in the inflammatory process and are used for a variety of allergic disorders. With its effect on suppressing vasodilatation and swelling, antihistamines are used commonly for rhinosinusitis. First-generation H1 receptors have a 45% homology with human muscarinic receptors^[20],[21] making it potentially antimuscarinic, which can lead to anticholinergic adverse effects such as urine retention. Second-generation H1 antihistamines were considered much safer, with their larger molecules that cannot pass the blood-brain barrier and cannot bind to muscarinic receptors. However, cases of urine retention were still reported, with the mechanism unknown.^[22]

In this study, we studied the changes in voiding function after pseudoephedrine and antihistamine use in men without known voiding dysfunction; we compared the effects of these two drugs. Although no cases of AUR were reported, around 52% of patients showed increased IPSS-T. Another important factor in male voiding dysfunction is prostate enlargement. Age plays a crucial role in prostate size; therefore, we divided our patients into two groups according to age (≥50 and <50 years old). Age was therefore shown to be a potential risk factor for pseudoephedrine-related urine retention, as the IPSS-T significantly increased in patients aged ≥50 years after receiving pseudoephedrine. This result is consistent with the outcome of our previous study,^[7] which confirmed the risk of prescribing pseudoephedrine to older men. Interestingly, the IPSS-V significantly increased in younger patients after prescribing antihistamines. Further studies are required to determine the cause.

To obtain more objective data, we measured postvoiding volume before and after medication use in all patients. When we divided the patients into mild and moderate-to-severe groups based on the IPSS-T (≤7 or > 7) before medication use, we found a significant increase in the PVR after pseudoephedrine use in the IPSS-T > 7 groups. This indicates that, apart from old age, poor baseline voiding function is also an important risk factor and may cause severe urine retention during pseudoephedrine treatment. Conversely, no significant changes were observed in the antihistamine group, which may be related to the use of second-generation antihistamines. Although the change of PVR was statistically significant, the increase was only 7.13 ml, which may not be clinically significant. As pseudoephedrine causes contraction of internal sphincter and relaxation of bladder smooth muscle, patients often experience voiding difficulty, resulting in an increase in the IPSS score. However, with compensating methods such as increasing abdominal pressure and lengthening voiding time, the change of PVR may not be so clinically significant.

Limitations

There are some limitations in this study. First, only male patients were included in this trial; therefore, we do not know whether these two drugs will have the same effects on women. Second, although the IPSS and PVR increased, only two patients sought medical help for voiding difficulty. Studying the clinically significant risks requires a much larger sample size. Third, using only PVR as an objective measurement was insufficient as PVR alone cannot indicate the mechanism of the effect of medication on different sites such as the bladder, bladder neck, or internal sphincter. Uroflowmetry and urodynamic studies will be required for a more specific investigation into the effects of both drugs.

Conclusion

Both pseudoephedrine and antihistamine do not significantly affect the general male population as far as the IPSS is concerned. However, pseudoephedrine could worsen the IPSS-T in elderly men, while antihistamines could worsen the IPSS-V in younger men. In male patients with an IPSS-T >7 (whom we considered as self-unaware voiding dysfunction patients), pseudoephedrine may worsen urine retention and increase PVR. With regard to voiding difficulty, while treating male patients with rhinitis, it may be safer to prescribe antihistamines to the elderly and pseudoephedrine to patients younger than 50 years. Extra precautions must be followed when prescribing pseudoephedrine if the patient reports voiding difficulty.

Acknowledgment

The authors would like to thank for the statistical assistance and acknowledge the support of the Maintenance Project of the Center for Big Data Analytics and Statistics (Grant CLRPG3D0045) at Chang Gung Memorial Hospital for statistical consultation and data analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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