Introduction

Guaifenesin (glyceryl guaiacolate ether, 3-(2-methoxyphenoxy)-1,2-propanediol, Figure 1) is commonly marketed as an expectorant for the treatment of cough and congestion symptoms related to acute upper respiratory tract infections (URTIs) and bronchitis. Originally derived from the guaiac tree, it is believed to have been used for medicinal purposes by Native Americans as early as the 16th century. [1] Originally approved by the US Food and Drug Administration (FDA) in 1952, it has been available OTC since 1989 and widely promoted to the public, most often in combination with cough suppressants, decongestants, and antihistamines. Guaifenesin is marketed under multiple brand names including Mucinex?and Robitussin? and has been found as an ingredient in at least 127 OTC cough and cold medications including a vast array of combination products. [2-3]

Pharmacological action

Guaifenesin enjoys a distinction as the only expectorant available in the United States without a prescription—an orphan in the pharmacopeia. While it has been approved by the FDA for this purpose its mechanism of action is not fully understood. One theory suggests that guaifenesin activates vagal afferent neurons in the gastric mucosa, leading to re?exive stimulation of airway mucous gland secretion and enhanced mucus hydration. [1] This may simultaneously increase volume and reduce viscosity, making it easier for mucus to be cleared through coughing and ciliary movement in the respiratory tract. It is classiffed as an expectorant rather than a mucolytic agent based on its ability to reduce mucus viscosity while increasing sputum volume, thereby promoting more effective coughing and expectoration.

Pharmacokinetics

Guaifenesin pharmacokinetics have been assessed following single and multiple dosing in adults. Following single-dose oral administration of an immediate-release formulation, peak plasma concentrations were observed at ~0.7 hours and the terminal exponential half-life (t_1/2,z) was ~0.8 hours. Over the range of 600 to 1200 mg, the maximum plasma concentration (C_max) and area under the curve from time zero to infinity (AUC) appeared to increase in proportion to dose. Following multiple-dose oral administration of an immediate-release formulation, steady-state appeared to be rapidly achieved (by the time of the first post-dose observation period), consistent with a short (t_1/2,z), and with a steady-state fluctuation index of ~3 ((C_max-C_min)/C_avg where C_min is the trough concentration at the end of the dosing interval and C_avg is the average concentration over a dosing interval). Following oral administration, guaifenesin is primarily metabolized with β-(2-methoxyphenoxy) lactic acid as the major urinary metabolite.[4] After oral administration, it is absorbed from the stomach and intestines and reaches its peak blood concentration within 1-3 hours. The recommended doses range from 400 to 1200 mg/d, but doses up to 2400 mg/d may be needed for some patients [5-6]. Conventional dosage forms of guaifenesin with 3-4 administrations per day have been used for long time due to its short t_1/2.

Controversy over therapeutic efficacy[3,5]

Few studies have evaluated the efficacy of guaifenesin for symptoms relating to mucus congestion in patients suffering from acute respiratory conditions . The lack of clinical data from randomized clinical trials has limited recommendations for use in current treatment guidelines other than for sinusitis and cough. However, this has not stopped physicians and patients from using guaifenesin to treat mucus-related symptoms. The limited published data available on the efficacy of guaifenesin for respiratory ailments have focused on symptoms that may be expected to improve with an expectorant,such as cough, chest congestion, and difficulty raising mucus. One small, placebo-controlled trial in 23 HIV-infected patients published in 1992 reported thinner postnasal discharge and decreased nasal congestion after treatment with guaifenesin, 2400 mg/d for 3 weeks (n=12), based on subjective reports from patients in the study [7]. 

The view of guaifenesin as an effective expectorant is challenged by recent evidence. Clinicians should critically assess its use, inform patients on the state of evidence for its efficacy, and consider emerging alternative treatments.

References

1. Albrecht HH, Dicpinigaitis PV, Guenin EP. Role of guaifenesin in the management of chronic bronchitis and upper respiratory tract infections. Multidiscip Respir Med. 2017;12:31.

2. McCoul ED. Assessment of pharmacologic ingredients in common over-the-counter sinonasal medications. JAMA Otolaryngol Head Neck Surg. 2020;146(9):810‐815.

3. Eyassu DG, McCoul ED. Guaifenesin: The Ubiquitous Orphan. Otolaryngol Head Neck Surg. 2024;171(4):1260-1261.

4. Thompson GA, Solomon G, Albrecht HH, Reitberg DP, Guenin E. Guaifenesin Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years. J Clin Pharmacol. 2016;56(7):894-901.

5. Storms W, Farrar JR. Guaifenesin in rhinitis. Curr Allergy Asthma Rep. 2009;9(2):101-106.

6. Yuta A, Baraniuk JN: Therapeutic approaches to mucus hypersecretion. Curr Allergy Asthma Rep 2005; 5:243–251.

7. Wawrose SF, Tami TA, Amoils CP. The role of guaifenesin in the treatment of sinonasal disease in patients infected with the human immunodeficiency virus (HIV). Laryngoscope. 1992;102(11):1225-1228.