Substitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An illogical way to control methamphetamine abuse

Abstract

The aim of this review was to investigate the rationale for replacing the nasal decongestant pseudoephedrine (PDE) with phenylephrine (PE) as a means of controlling the illicit production of methamphetamine. A literature search was conducted in electronic databases and use of textbooks. Restrictions have been placed on the sale of PDE in the USA in an attempt to control the illicit production of methamphetamine. This has caused a switch from PDE to PE in many common cold and cough medicines. PE is a poor substitute for PDE as an orally administered decongestant as it is extensively metabolized in the gut and its efficacy as a decongestant is unproven. Both PDE and PE have a good safety record, but the efficacy of PDE as a nasal decongestant is supported by clinical trials. Studies in the USA indicate that restricting the sale of PDE to the public as a medicine has had little impact on the morbidity and number of arrests associated with methamphetamine abuse. Restricting the sale of PDE in order to control the illicit production of methamphetamine will deprive the public of a safe and effective nasal decongestant and force the pharmaceutical industry to replace PDE with PE, which may be an ineffective decongestant. Restrictions on sales of PDE to the public may not reduce the problems associated with methamphetamine abuse.

Sympathomimetics are widely used as a systemic nasal decongestant in over-the-counter (OTC) common cold and flu medicines. The UK OTC Directory (2005/2006) lists 21 cough and cold medicines that contain phenylephrine (PE), 34 that contain pseudoephedrine (PDE) and one containing ephedrine [1]. In 1959 there were 15 sympathomimetic oral medicines in use in the USA as nasal decongestants [2]. With the recent withdrawal of phenylpropanolamine in most countries, due to concerns about abuse as a diet aid and possible links to cerebrovascular stroke [3], there are now only two systemic nasal decongestants in common use worldwide, PDE and PE. Concerns about the illicit conversion of PDE into methamphetamine [4, 5] have obliged pharmaceutical companies in the USA to switch PDE to PE in nasal decongestant products because of the restrictions imposed on the sale of PDE to the public. In the USA the Combat Methamphetamine Epidemic Act of 2005 bans OTC sales of medicines that contain PDE and requires purchasers of ‘behind the counter’ PDE to present a photo identification and to provide personal information in a log which will be kept by the seller for at least 2years. The severe restrictions imposed on the sale of PDE in the USA may be copied by the regulatory authorities in other countries and this may lead to the loss of PDE as a common cold medicine. The efficacy and safety of PDE as a systemic nasal decongestant in syrup and tablet formulations are well documented [6–9], but the efficacy of PE as a nasal decongestant has received little attention in the literature. The aim of this review was to compare the efficacy and safety of the two nasal decongestants and highlight important differences, rather than provide an in-depth review of each medicine.

Methods

Medline and Web of Science databases were searched using the terms ‘phenylephrine’ or ‘pseudoephedrine’ paired with either ‘decongestant’ or ‘nasal’. The author's own bibliography and textbooks were also used to find relevant publications. Key publications were also used in the Web of Science citation search. The bibliographies of all relevant publications were used to find any references that were not found in the electronic searches. Documents provided by the Propietary Association of Great Britain (PAGB) were consulted and the UK Medicines and Healthcare products Regulatory Agency (MHRA) and USA Food and Drugs Administration (FDA) were also approached for information on PE.

Pharmacology and metabolism

PE and PDE are sympathomimetic vasoconstrictors that are closely related to adrenaline in structure, as illustrated in Figure 1. PE differs chemically from adrenaline only in the absence of one hydroxyl group from the benzene ring. PDE is a stereoisomer of ephedrine and is used commercially as the (+)-entantiomer [10] PDE hydrochloride. PE contains a single chiral carbon atom and thus exists as an enantiomeric pair of stereoismers. It is used commercially as the (−)-enantiomer [10] as PE hydrochloride.

Figure 1.

Chemical structure of adrenaline, phenylephrine, pseudoephedrine and methamphetamine

PE is a relatively selective α₁ agonist. It has weak α₂ adrenoceptor agonist activity and low β agonist activity. Most of the α₁ agonist activity is due to a direct action on α receptors with relatively little indirect effect via noradrenaline release [11]. PDE has mainly indirect effects on adrenergic receptors. It has indirect agonist activity, particularly on cardiac β receptors and peripheral α₁ receptors, through displacement of noradrenaline from the cytoplasmic pool [11].

Sympathomimetcs such as PE and PDE are nasal decongestants because of their vasoconstrictor activity. Therefore, there is always a risk of cardiovascular side effects. However, nasal blood vessels have been shown to be around five times more sensitive than the heart to the effects of circulating adrenaline [12] and this may explain how PDE in the low doses used in OTC medicines may cause nasal decongestion with minimal cardiac effects.

The pharmacology and metabolism of PE and PDE are summarized in Table 1. Both PE and PDE are well absorbed from the gut. The main difference between the decongestants is that after oral administration PE is subject to extensive presystemic metabolism by monoamine oxidase in the gut wall [10, 13]. As a consequence of metabolism, systemic bioavailability of PE is only around 40% [13]. Only about 3% of an oral dose of PE is excreted unchanged in the urine [10]. PDE is resistant to the actions of monoamine oxidase and between 43% and 96% of an oral dose is excreted unchanged in the urine [10]. In oral OTC doses, PE and PDE have minimal effects on the cardiovascular system [9, 14, 15]. When administered intravenously, PE causes an increase in arterial blood pressure and bradycardia [16] and may also cause coronary vasospasm. The threshold dosage of PE administered orally in man for any effects on the cardiovascular system is about 50 mg and at this dose PE causes a decline in heart rate and a slight increase in arterial blood pressure [14]. OTC doses of 60 mg PDE cause a slight increase in heart rate with no detectable change in blood pressure [9, 15].

Table 1.

Comparison of pharmacology and metabolism of phenylephrine and pseudoephedrine [10, 11, 13, 15, 16]

	Phenylephrine	Pseudoephedrine
Adrenoceptor activity	Mainly α1	β and α1 indirect
CNS activity	None	weak stimulant
Presystemic metabolism	Gut and liver	None
Excretion in urine	3% unchanged	90% unchanged
Cardiovascular effects	Hypertension bradycardia	Hypertension bradycardia
Maximum dosage	10–12.2 mg every 4 h	60 mg every 4–6 h
Tmax (h) plasma	1.0–1.3	1.9
t1/2	2.0–3.0	5.4

PDE is reported to have a greater incidence of central nervous sustem (CNS) stimulant effects than PE [11, 17] and this fits in with the differences in chemical structure as shown in Figure 1. PDE differs from PE in having one less hydroxyl group and this loss would be expected to increase the lipid solubility and CNS availability of PDE compared with PE.

Comparison of the pharmacology of PE and PDE indicates that PE is a potent vasoconstrictor agent because of its direct α agonist activity, whereas PDE is a less potent vasoconstrictor as its vasoconstrictor effects are due to indirect actions via noradrenaline release [11]. The tolerability of PE as an oral nasal decongestant is likely to be due to its poor access to the systemic circulation rather than to its pharmacological profile.

Efficacy

No support has been found in the literature in the public domain for the efficacy of PE as a nasal decongestant when administered orally. Approaches to the UK and USA regulatory authorities (MHRA and FDA) have not provided any information in the public domain. The 1976 FDA monograph on OTC cold and cough products reports that PE is an effective nasal decongestant on the basis of reports on in-house studies on PE provided by representatives of pharmaceutical companies [18]. On the basis of these in-house studies, the FDA approved PE as an effective nasal decongestant. This decision by the FDA on the efficacy of PE was questioned by a comment to the FDA in 1985, which stated that the unpublished studies split evenly between mild successes and total failures; in addition, the comment questioned the oral bioavailability of PE and recommended that the FDA should not accept PE as an oral decongestant [19]. Despite the concern expressed about the efficacy of PE as an oral decongestant, the FDA maintained its approval for PE as an effective nasal decongestant and PE is accepted as an effective oral nasal decongestant in the FDA's final conclusions on nasal decongestants published in 1994 [20].

The standard pharmaceutical textbooks provide information about the efficacy of PE as a vasoconstrictor used during surgery to counteract hypotension, and as eye drops to dilate the pupil, but provide no information about the efficacy of PE as a nasal decongestant [11, 21]. However, the efficacy of phenylephrine formulated as a topical nasal decongestant nasal spray (0.25–0.5% w/v) is supported by several studies [22–24]. The only study involving an oral dose of PE reported that 10 mg PE was no more effective than placebo as a nasal decongestant [17] (the study also reported a similar lack of effect for PDE), and a comprehensive recent Cochrane review provides no support for the efficacy of PE [8]. In view of the extensive metabolism of PE in the gut wall, it seems unlikely that PE is an effective oral nasal decongestant and more clinical trials are needed to support any claims of efficacy.

Clinical studies of PDE provide sufficient information to support the efficacy of an OTC dose of 60 mg as a nasal decongestant. A single dose of 60 mg PDE has been shown to reduce nasal airway resistance in patients suffering from nasal obstruction in several trials [7, 9, 25, 26] and also to reduce nasal airway resistance in healthy volunteers after histamine challenge [27]. PDE 60 mg has also been reported to be an effective treatment for nasal congestion associated with common cold when administered in multiple doses over several days [9, 28].

Safety

Many millions of patients are exposed to PE and PDE in common cold medications each year, as these decongestants are found in numerous common cold and cough medicines. It is difficult to be confident about the true incidence of side effects and adverse events associated with PE and PDE, as they are usually formulated as combination medicines with analgesics and antihistamines. However, despite the great exposure of the general public to PE and PDE there is no consistent history of adverse events in the medical literature, and this indicates that PE and PDE in various OTC combination medicines are safe if taken as indicated.

As with all sympathomimetics, PE and PDE should not be taken by patients suffering from hypertension, hyperthyroidism or heart disease because of the vasoconstrictor effects of the medicines. Similarly, patients suffering from Raynaud's syndrome or taking medicines that inhibit monoamine oxidase (MAO) should consult their doctor before taking PE. PE and PDE may cause retention of urine in patients with prostate problems.

There is no evidence that PE and PDE have adverse effects on the cardiovascular system in normotensive subjects and PE and PDE are also reported to be safe in patients with controlled hypertension [29, 30], although there are scant clinical data on the topic. Some concern has been expressed that any switch from PDE to PE may expose patients with cardiovascular disease to a medicine whose safety profile is not so well documented, but, given the long history and wide use of these nasal decongestants, this concern seems unfounded [31].

Concern has also been expressed about the inadvertent use of PE by patients taking MAO inhibitors, as inhibition of this enzyme could reduce the metabolism of PE and therefore exacerbate any cardiovascular effects [32]. However, given the present-day limited use of MAO inhibitors and the well-known dangers of sympathomimetics, this seems to be a low risk.

PDE is associated with an increased incidence of CNS adverse events compared with PE, but when taken in OTC doses the most commonly reported side effect of PDE is insomnia [28]

Discussion and conclusions

PE and PDE have been used as oral decongestants for over 50 years in a large range of medicines for the treatment of nasal congestion associated with common cold and flu. There is support in the literature for the efficacy of PDE as an orally administered nasal decongestant [6–9, 25–27], but no support for the efficacy of oral PE. PE has historically been registered in the UK as a combination medicine without the need for any clinical data to support efficacy, and in the USA the monograph depends on unpublished studies. The lack of efficacy data indicates that PE in OTC doses has not been shown to be an effective decongestant and more clinical trials in the public domain are needed to study its nasal decongestant effects. Both PE and PDE can be considered safe in OTC doses and there is little to choose between the medicines as regards the safety profile, with no detailed accounts of the frequency or severity of adverse effects being available [11].

The problems associated with the illicit conversion of PDE to methamphetamine may cause pharmaceutical companies throughout the world to switch PE for PDE and therefore increase the number of OTC medicines that contain PE. Studies in the USA indicate that it is the large-scale production of methamphetamine rather than public sales of PDE which needs to be targeted in order to reduce the morbidity [33] and the number of arrests associated with methamphetamine use [34]. Restricting the sale of PDE in order to control the illicit production of methamphetamine will deprive the public of a safe and effective nasal decongestant, and force the pharmaceutical industry to replace PDE with an unproven nasal decongestant, PE, despite reports that restriction on sales of PDE to the public may not reduce the problems associated with methamphetamine abuse.

Conflict of interest

The author has acted in the past as a consultant to pharmaceutical companies that market nasal decongestants (Procter & Gamble, GlaxoSmithKline, Pfizer, Reckitt Benckiser, Boots Health Care and Bayer)