Continuing Education Lesson
Every day, millions of people across the country rely on effective over-the-counter (OTC) cold and allergy medications containing pseudoephedrine (PSE) for their indicated use; however, some people buy these same medications with the intention of converting PSE into methamphetamine (METH). METH addiction is a chronic relapsing disorder, which has been linked to the dysregulation of brain processes that influence memory, behavior, and motor function.1 Although METH was first synthesized from ephedrine by Nagai Nagayoshi in 1893,2 it did not reach widespread use until World War II.3 Prior to the war, the neuropsychiatric manifestations of METH were not yet established; consequently, the clinical effects of the drug, including increased attentiveness and the reduced need for sleep, seemed ideal for bomber pilots and soldiers during battle. However, the experiment failed because soldiers developed behavioral and functional disturbances, such as irritability, uncontrolled aggression, and memory impairment. Despite these documented concerns, METH was still prescribed postwar by some physicians for the treatment of depression, narcolepsy, and obesity.3
In the early 1960s, amid concerns of illegal METH use, pharmaceutical companies withdrew their injectable formulations of METH; notably, a 5 mg oral methamphetamine formulation, Desoxyn, is still available as schedule II controlled substance. As a result, motorcycle gangs and other subcultures became largely responsible for the manufacturing and distribution of METH, relying on the precursor chemical phenyl-2-propanone (P2P) for production.4 It was from the transportation in the crank cases of motorcycles that METH got its street name crank.4 With the rise of the Controlled Substances Act of 1970, which labeled P2P as a schedule II controlled substance, METH manufacturing and distribution by subcultures was disrupted and a national education campaign was launched to heighten public awareness with regard to the neuropsychiatric complications associated with METH's immediate and long-term use.3
Nevertheless, the use of METH began rising again in the 1980s, due to a smokable formulation that could be produced in small clandestine labs. In the early 1990s, METH became one of the most highly abused stimulant medications among illicit drug users, along with crack, heroin, and cocaine,5 which ultimately became the foundation of the METH crisis that dominates the national landscape today. To help counter this resurgence, Congress passed the Comprehensive Methamphetamine Control Act of 1996 and the Combat Methamphetamine Epidemic Act of 2005 (CMEA), which placed restrictions on the purchase and availability of precursor chemicals required to develop METH, including PSE, ephedrine, and phenylpropanolamine (PPA).6
Despite these efforts, the market for amphetamine-type stimulants (ATS) appears to be expanding as ATS seizures are increasing and new markets are developing. While METH is an ongoing issue at the global level, most METH laboratories continue to be reported by the United States, where the number of laboratories increased 4-fold, from 2574 in 2010 to 11,116 in 2011.7 Additionally, the amount of METH seized globally increased from 51 tons in 2010 to 88 tons 2011, with the United States and Mexico responsible for more than 60% of the seizures.7
METH, also referred to as chalk, ice, or crank, is a powerful stimulant that affects the central nervous system (CNS). It is available in several forms and can be smoked, snorted, injected, and orally ingested.8 Because it is lipophilic, METH readily crosses the blood-brain barrier where it affects several biogenic monoamines, including serotonin (ST), dopamine (DA), and norepinephrine (NE), which influence mood, reward, motivation, and adrenergic activity.9
METH enhances the release of monoamines from nerve terminals, as well as reduces their enzymatic breakdown in the synaptic cleft, causing a rapid and sustained increase in the intra- and extracellular concentrations of ST, DA, and NE.10 In contrast to cocaine, which is rapidly metabolized and removed from the body, METH has a half-life of nearly 12 hours and, therefore, a much longer duration of action.9 This causes increased arousal and excitability, as well as an enhanced ability to concentrate8; but, the sustained and repeated release of monoamines is also largely responsible for the adrenergic and neurologic sequelae associated with METH. These effects include tachycardia, hypertension, psychomotor agitation, stroke, and, in extreme cases, hyperthermia.9 With repeated use, METH damages neurons and depletes the brain's stores of DA and ST, which is likely a contributing factor to METH's high abuse potential; without the drug, addicts may experience the impaired ability to experience pleasure, which often leads to depression, anxiety, and psychosis.1,9 Common long-term complications of METH abuse include formication (the sensation that insects are crawling on the skin), punding (nongoal-directed repetitive activity), dyskinesia, and dental caries (referred to as METH mouth).9 Table 1 lists additional short- and long-term effects associated with METH abuse. Because pharmacists and other pharmacy personnel are frequently involved in face-to-face interactions with consumers regarding the purchase of PSE, a heightened awareness of the common symptoms/effects of METH abuse is likely to result in more responsible decision making at the point of sale.
METHAMPHETAMINE PRODUCTION AND ECONOMIC COSTS
The difference between METH (C10H15N) and ephedrine (C10H15NO) or PSE (C10H15NO) is a single oxygen atom. Therefore, the following chemical reduction methods that convert ephedrine/PSE into METH target the oxygen atom for removal11: (1) The Birch method, used frequently in the Midwest because of the increased access to anhydrous ammonia (a chemical used by farmers as fertilizer), is a chemical reduction reaction capable of producing large quantities of METH; (2) the red phosphorous method is a chemical reduction reaction using red phosphorus/hydriodic acid and is the primary reduction method used in Mexico-based super laboratories; lastly,(3) the one-pot method, also known as shake and bake, is a simplified method of the Birch reaction that involves mixing precursor chemicals with raw materials in a container that can be resealed, such as a 2-liter bottle. This method requires minimal training, enabling individuals to make the drug quickly. Another precursor drug, PPA (C9H13NO), is similar in molecular structure to ephedrine and PSE; however, when PPA is chemically reduced, the end product is dextroamphetamine.12 PPA was removed from the market because it was shown to increase the risk of hemorrhagic stroke13; however, it is still used in veterinary medicine for the treatment of urinary incontinence in dogs.14
While METH production requires limited expertise and training, the materials used in the process are toxic and mistakes can result in an explosion or injury. METH-related incidents accounted for approximately 103,000 emergency department visits in 2011.8 Common ingredients and equipment that are used to make METH are listed in Table 2.15 For each manufactured pound of methamphetamine, an estimated 5 to 6 pounds of hazardous waste are generated, posing significant environmental and biological risks to surrounding communities.16 Because many of the necessary items can be purchased at pharmacies, pharmacists should have a basic understanding of the ingredients and equipment used in the manufacturing process, so they can more effectively assist law enforcement by identifying suspicious individuals and reporting their concerns to the appropriate authorities. Moreover, the economic burden of METH in the United States is substantial, with estimates ranging from $16.2 billion to $48.3 billion.17 These figures include the estimated costs associated with environmental cleanup, drug treatment, the burden of addiction, lost productivity, crime, and criminal justice costs, as well as child endangerment.17
FEDERAL LAW and ELECTRONIC TRACKING SYSTEMS
The CMEA was signed into law on March 9, 2006 and regulates the sale of nonprescription medicines containing PSE, ephedrine, or PPA (referred to as schedule-listed chemical products).18 The CMEA sets the daily sales limit of schedule-listed chemical products at 3.6 grams per purchaser, regardless of the number of transactions, and not more than 9 grams may be sold to a single purchaser over a 30-day period. Notably, if an individual were to use 240 mg of PSE per day (i.e., the maximum recommended daily dosage) over a period of 30 days, a total of 7.2 grams of PSE would be consumed, which is less than the 30-day limit established by CMEA. For mail-order and mobile retail vendors, the 30-day limit is reduced to 7.5 grams per purchaser.18 In addition, a schedule-listed chemical product cannot be sold to a purchaser unless they are able to present photo identification (ID) issued by a state or the federal government. Once a photo ID is provided, the pharmacist must then determine that the individual's name entered into the logbook matches the name on their photo ID and that the date and time are entered correctly.18 Also, schedule-listed chemical products must be kept behind the counter or in a locked cabinet, so customers do not have direct access to these products, and all nonliquid dosage forms must be packaged in 2-unit blister packs.19
The statute also requires a seller to maintain a logbook, written or electronic, with a list of applicable sales, including the following information: (1) schedule-listed chemical products sold by name; (2) quantity sold; (3) names and addresses of purchasers; and (4) the date and time of sale.18 Moreover, logbook information must be stored/maintained for a minimum of 2 years. It should be kept in a secure area and its contents may only be shown to local, state, and federal law enforcement. It must contain a notice to individual purchasers indicating that false information may result in a maximum $250,000 fine and imprisonment up to 5 years.18 Notably, the logbook does not apply to any purchase of a single package that contains less than 60 mg of PSE; this single package 60 mg exception does not apply to ephedrine or PPA.19 In addition, CMEA mandates sellers to self-certify to the Attorney General that individuals who are responsible for selling schedule-listed chemical products understand and are in compliance with requirements regarding transactional limits, blister packs, storage, photo identification, and logbook documentation.18 In the event that pharmacy personnel do not abide by the rules of the law, PSE may be permanently removed from the pharmacy and those involved may incur civil penalties.15,18
Faced with the limitations of handwritten logbooks, some states have adopted electronic tracking systems to help monitor PSE sales. For instance, 24 states have enrolled in a centralized electronic tracking system called the National Precursor Log Exchange (NPLEx), which is a real-time electronic tracking system used by pharmacies and law enforcement to track sales of scheduled listed chemical products.20 Importantly, data entered into NPLEx is available to all participating states, which carries the potential to reduce smurfing (i.e., a process involving individuals that travel to multiple stores to purchase the legal limit of PSE for illicit drug use) and, thereby, reduce METH manufacturing. States can enroll and maintain the partnership with NPLEx at no cost, provided state governments pass appropriate regulations and legislation.20 Although NPLEx is commonly adopted as a statewide system, individual pharmacies may enroll in the program for a nominal fee, which allows them access to PSE sales in other states, as well as participating pharmacies.15 Several states have reported evidence that demonstrates the positive impact of electronic tracking systems. For example, in the state of Kentucky, the NPLEx tracking system has helped block the sale of approximately 10,000 grams of PSE per month.21 Additionally, Georgia pharmacies that voluntarily participate in the Georgia Methamphetamine Intelligence System (GMIS) identified 126 people who purchased more than the legal limit of PSE over a 4-month period.21 The extent and usefulness of the data already collected from the new tracking systems must be assessed and the long-term benefits remain uncertain; however, it is critical that novel methods of deterring METH manufacturing continue to be produced and evaluated as another method to reduce the health risks and environmental contamination associated with its use.
Importantly, if a seller's state has stricter laws regarding the sale of schedule-listed chemical products compared with the federal legislation already implemented, the stricter state laws must be followed in addition to the federal law.19 For example, Mississippi and Oregon have implemented the strictest PSE laws to date, which mandate patients to present a prescription to the pharmacist for products containing PSE.22 As a result, each state has observed a steady reduction in Meth-related incidents. The Mississippi Bureau of Narcotics reported an estimated 67% reduction in METH-related cases statewide since the law was implemented in 2010.21 Additionally, DEA officials in Oregon reported a 94% decrease in METH-related incidents from 2005 to 2009.21 Although the state of Oklahoma has yet to implement a prescription only law for PSE, they have implemented tougher restrictions for METH offenders; they have imposed the rule that individuals with prior offenses may not possess PSE at all. To further enforce this policy, the Oklahoma State Board of Pharmacy and the Oklahoma Bureau of Narcotics and Dangerous Drugs have developed a METH registry, which blocks the sale of PSE to anyone with a METH-related drug offense.23 At the point of sale, the purchaser's name is checked against the registry and the sale is cancelled if they are identified in the system. Additionally, the state of Arkansas passed a bill indicating that pharmacists must determine whether or not a purchaser has a clear medical need for PSE before a transaction can be completed, which further emphasizes the importance of pharmacists being able to recognize the short- and long-term effects of METH abuse.24 Following the lead of the states mentioned previously, more state governments are also considering stricter regulations with regard to PSE, which will potentially reduce the illicit use of METH while making PSE less available to those who use it for its intended purpose. Therefore, it is important that pharmacists remain up-to-date with their state's laws regarding the regulation of PSE and other schedule-listed chemical products.
Because of existing federal and state laws, as well as national campaigns targeting the illicit use of METH, PSE's efficacy in treating nasal congestion is often overlooked. Nasal congestion is a vascular process that involves swelling of the nasal mucosa which impedes normal breathing.25 Decongestants constrict the mucosa allowing for normal breathing to resume.26 Phenylephrine and PSE are the 2 primary oral nonprescription medications available to consumers for the relief of nasal congestion, but consumers are frequently unclear regarding the differences between the 2 products. Consequently, pharmacists are in a unique position to address questions and concerns regarding phenylephrine and PSE.
As a result of CMEA, some pharmaceutical manufacturers have substituted phenylephrine for PSE in their OTC cough/cold/allergy products because phenylephrine cannot be converted to METH and it can be sold in pharmacies and grocery stores without restrictions. Phenylephrine is a selective α1-adrenergic receptor agonist whose primary pharmacologic effect is the vasoconstriction of blood vessels, including the nasal mucosa, which decreases blood volume and leads to nasal decongestion.26 Because phenylephrine undergoes significant presystemic metabolism by monoamine oxidase in the gut wall, the oral bioavailability of phenylephrine in adults is only about 40%; although it can be administered intranasally, which increases the bioavailability of the drug at the site of action.26,27 While intranasal formulations, such as phenylephrine, oxymetazoline, and propylhexedrine, increase bioavailability of the active ingredient and produce more localized effects, they are not recommended for use beyond 72 hours because of the potential to develop rhinitis medicamentosa, which is a drug-induced nonallergic form of rhinitis that involves aggravation of the nasal mucosa.27
In December 2007, the FDA held a public advisory committee meeting to evaluate the current safety and efficacy data for the OTC dose of oral phenylephrine. The Nonprescription Drugs Advisory Committee indicated that, while additional studies would be useful for evaluating select doses of phenylephrine, the 10 mg dose currently included in the OTC monograph is both safe and effective as an oral decongestant28; notably, the monograph was approved in 1976 based on unpublished scientific data provided by pharmaceutical manufacturers.25,28 Moreover, a 2007 meta-analysis, which included 7 single-dose, randomized, placebo-controlled studies of phenylephrine 10 mg, concluded that 4 out of 7 studies demonstrated significantly reduced nasal airway resistance (NAR) associated with the common cold (P ≤ 0.05).29 Furthermore, a trial that compared the decongestant effect of a single dose of phenylephrine with placebo with PSE in patients with seasonal allergic rhinitis revealed that phenylephrine was not significantly different from placebo for reducing nasal congestion (P = 0.56); however PSE was significantly more effective than both placebo (P < 0.01) and phenylephrine (P = 0.01).30 Studies involving oral phenylephrine 10 mg have produced mixed results and the overall effectiveness of phenylephrine as an oral OTC nasal decongestant appears to be uncertain.
PSE is an indirect agonist at both β1- and α1-adrenergic receptors, which acts primarily through intracellular displacement of norepinephrine from the cytoplasm.26 PSE is resistant to monoamine oxidase and 43% to 96% of an oral dose is excreted unchanged in the urine.26 Additionally, PSE has been reported to have greater central nervous system penetration compared with phenylephrine, which may result from PSE having one less hydroxyl group; this difference in molecular structure would be expected to make PSE more lipid soluble, increasing its availability to the CNS.26
While early studies investigating PSE's decongestant effects produced conflicting results, multiple randomized placebo-controlled studies have reported significant improvements in both objective and subjective measures of nasal congestion.30-32 In a placebo-controlled, double-blind, randomized trial that evaluated the efficacy of PSE for relieving the nasal congestion associated with a common cold, a single 60 mg dose of oral PSE significantly improved symptoms of congestion compared with placebo at times 60, 90, 120, and 150 minutes after the dose was administered.31 Both nasal cross-sectional area and nasal volume increased significantly compared with placebo (P = 0.018 and P = 0.003, respectively). In a separate placebo-controlled, double-blind, randomized trial that evaluated single and multiple doses of PSE, patients who were administered PSE showed significant reductions in NAR on day 1 and on day 3 compared with those taking a placebo (P = 0.006 and P < 0.001, respectively). Subjective measures (e.g., symptomatic relief) were substantially improved in the PSE group as compared with the placebo group on day 1 but not at day 3.32
When taken at recommended doses, studies indicate PSE and phenylephrine may be used safely to treat nasal and sinus congestion; the majority of reported adverse effects appear to be related to higher doses or patients with underlying conditions that enhance the pharmacologic effects of phenylephrine and PSE.26,28 As with other medications that potentiate the sympathetic nervous system, PSE and phenylephrine should be used with caution in patients with underlying cardiovascular disease, hyperthyroidism, urinary retention and prostate problems, as well as patients taking monoamine oxidase inhibitors. In addition, sleep-related disturbances appear to be more frequently reported with PSE.26
While PSE appears to be a safe and effective medication for nasal congestion, many patients that use PSE for its intended purpose are at a disadvantage because of state laws regarding the availability of PSE. The PSE prescription-only law is 1 example. The time and effort associated with scheduling and attending a medical appointment is an inconvenience by many in the United States, especially when OTC products have demonstrated therapeutic efficacy in treating nasal and sinus congestion. Therefore, consumers may choose to settle for decongestant products with phenylephrine as the active ingredient or topical products that carry the potential of causing rhinitis medicamentosa with repeated use. New extraction-resistant drug delivery formulations of PSE may help to mitigate these issues.
NEW DRUG FORMULATIONS
The United States retail sales of nonprescription drug products reached $17 billion in 2010, with OTC cough/cold/allergy products accounting for more than 700 million units sold.33 Notably, the FDA does not review and approve individual OTC medications; instead, they review the active ingredients of nearly 80 different therapeutic drug classes.34 Once an active ingredient has been reviewed and finalized by the Center for Drug Evaluation and Research (CDER) and its Nonprescription Drugs Advisory Committee, an OTC monograph is published in the Federal Register. These monographs define the safety, effectiveness, and labeling of all marketed OTC active ingredients and serve as a template for pharmaceutical manufacturers considering the development of OTC medications or new dosage formulations of existing drug products.34 If the monograph for an existing OTC medication is followed, a pharmaceutical company can make and market a new OTC medication formulation without the need for FDA pre- approval. Because of the ongoing controversy regarding METH abuse and addiction, 2 alternative OTC formulations of PSE have been developed in an effort to disrupt and mitigate the illicit making of METH, while remaining safe and effective when used to reduce nasal congestion.
Zephrex-D is a novel PSE formulation that uses Tarex, a patented extraction-resistant technology for the manufacture of oral medications, which is also used in the manufacture of opiate drug formulations to prevent misuse/abuse.35 When Tarex PSE is used in common METH-making practices, the resulting product from the initial extraction process is derailed, which interferes with the subsequent steps necessary for METH production.36 In an independent study that used the traditional 2-step process of creating METH, it was determined that only 0.5% of PSE from Zephrex-D was available to be converted into METH.37 When more advanced laboratory methods were applied to Zephrex-D, the yield was less than 2.0%.37 Notably, the small amount of METH that is produced during these processes is trapped in excipients that cannot be smoked, injected, or snorted. More than 87% of domestic clandestine METH labs utilize the one-pot manufacturing process and laboratory testing of Zephrex-D revealed that METH cannot be produced using this widespread method.37 In addition, Zephrex-D meets all FDA OTC monograph requirements for products containing pseudoephedrine hydrochloride.
Nexafed, another innovative PSE product, uses Impede technology, a unique polymer matrix that forms a thick gel when tablets are dissolved in solvents typically used in METH production processes, further limiting its purification.38 In laboratory testing that measured METH recovery using the one-pot method, the mean value of METH recovered from Nexafed was 38%, while the control (Sudafed) resulted in an average METH yield of 66%.11 Notably, in a pharmacokinetic study, Nexafed demonstrated bioequivalence to Sudafed, which indicates this product reached the systemic circulation at an equivalent rate and extent.11
Nexafed and Zephrex-D are indicated for temporary relief of nasal and sinus congestion and both are available as a 30 mg tablet with the following age-specific dosing recommendations: 1) adults may take 2 tablets every 4 to 6 hours; 2) children 6 to 12 years of age may take 1 tablet every 4 to 6 hours; 3) children younger than 6 years of age should not use this medication without consulting a doctor; and d) a maximum of 4 doses may be taken in a 24-hour period (8 tablets or 240 mg for an adult and 4 tablets or 120 mg for children 6 to 12 years of age).35,38 If these novel PSE drug formulations successfully serve to complicate their utility as precursor agents for the development of METH, perhaps, over time, it may not be as necessary to implement more stringent legislation regarding PSE availability to consumers.
RESPONSIBILITIES OF THE PHARMACIST
The aging and growth of the United States population, along with the recent changes in health care, are factors that are expected to increase the demand for health care services over the next several years. Since passage of the Affordable Care Act (ACA), an ever-increasing number of individuals have health insurance.39 As a result, primary care office visits are expected to increase by 15 million to 25 million visits per year by 2019.39 Because state laws are making PSE more difficult for those in the United States to obtain, with 2 states already mandating provider approval, pharmaceutical innovations that reduce illicit METH use while maintaining OTC standards of safety and efficacy are needed. Two novel PSE products were developed using unique extraction-resistant technology, both of which have demonstrated the ability to substantially reduce the amount of METH that can be extracted using the most common manufacturing methods. Pharmacists must be familiar with both Zephrex-D and Nexafed drug formulations to effectively counsel patients and other health care providers regarding the safety, efficacy, and METH deterring properties of each product. In addition, pharmacists should be aware of both the short- and long-term effects of METH abuse, as well as common ingredients and equipment used for the manufacturing processes, so they can better recognize customers that would abuse or divert these medications. Finally, because the number of METH labs is increasing and state PSE laws are becoming more stringent, pharmacists should review data explaining the specific policies, procedures, and recommendations in their state, as well as the existing federal laws that govern the sale and use of schedule-listed chemical products.
- Koob GF. The role of brain stress systems in addiction. Neuron. 2008;59(1):11-34.
- Nagai T, Kamiyama S. Forensic toxicologic analysis of methamphetamine and amphetamine optical isomers by high performance liquid chromatography. Z Rechtsmed. 1988;101(3):151-159.
- A Brief History of Methamphetamine—Methamphetamine Prevention in Vermont. Vermont Department of Health Web site. http://healthvermont.gov/adap/meth/brief_history.aspx. Accessed September 19, 2013.
- Gonzales R, Mooney L, Rawson RA. The methamphetamine problem in the United States. Annu Rev Public Health. 2010;31:385-398.
- Derlet RW, Heischober B. Methamphetamine. Stimulant of the 1990s? West J Med. 1990;153(6):625-628.
- Legal Requirements for the Sale and Purchase of Drug Products Containing Pseudoephedrine, Ephedrine, and Phenylpropanolamine. U.S. Food and Drug Administration (FDA) Web site. http://www.fda.gov/drugs/drugsafety/ informationbydrugclass/ucm072423.htm. Updated July 15, 2009. Accessed October 2, 2013.
- World drug report 2013. United Nations Office on Drugs and Crime (UNODC) Web site. http://www.unodc.org/unodc/ secured/wdr/wdr2013/World_Drug_Report_2013.pdf. Accessed October 1, 2013.
- Methamphetamine: abuse and addiction. National Institute on Drug Abuse Web site. http://www.drugabuse.gov/ publications/research-reports/methamphetamine-abuse-addiction. Updated September 2013. Accessed October 2, 2013.
- Rusyniak DE. Neurologic manifestations of chronic methamphetamine abuse. Neurol Clin. 2011;29(3):641-655.
- Cruickshank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine. Addiction. 2009;104(7):1085-1099.
- Brzeczko AW, Leech R, Stark JG. The advent of a new pseudoephedrine product to combat methamphetamine abuse. Am J Drug Alcohol Abuse. 2013;39(5):284-290.
- Logan BK. Amphetamines: an update on forensic issues. J Anal Toxicol. 2001;25(5):400-404.
- Phenylpropanolamine (PPA) information page. U.S. Food and Drug Administration (FDA) Web site. http://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm150738.htm. Updated September 3, 2010. Accessed Ocotober 8, 2013.
- Phenylpropanolamine hydrochloride [package insert]. Pensacola, FL: Pegasus Laboratories, Inc.;2010.
- Combating Methamphetamine Abuse. 2011;2009(course number 107). Pharmacist's Letter Web site. http://pharmacistsletter.Therapeutic research.com/ce/ceCourse.aspx?cs=&s=PL&pv=1&pc=09-107&quiz=. Accessed October 7, 2013.
- Community Impact from Methamphetamine. Vermont Department of Health Web site. http://healthvermont gov/adap/meth/community_impact.aspx. Accessed October 7, 2013.
- The Economic Cost of Methamphetamine Use in the United States, 2005. RAND Corporation Web site. http://www.rand.org/content/dam/rand/pubs/monographs/2009/RAND_MG829.sum.pdf. Accessed October 5, 2013.
- General Information Regarding The Combat Methamphetamine Epidemic Act of 2005 [Title VII of Public Law 109-177]. U.S. Department of Justice Drug Enforcement Administration: Office of Diversion Control Web site. http://www.deadiversion.usdoj.gov/meth/cma2005_general_info.pdf. Accessed September 21, 2013.
- Training required to sell drug products containing ephedrine, pseudoephedrine, and phenylpropanolamine. U.S. Department of Justice Drug Enforcement Administration: Office of Diversion Control Web site. http://www. deadiversion.usdoj.gov/meth/trg_retail_081106.pdf. Accessed September 15, 2013.
- Real-time tracking and blocking of meth precursors. National Precursor Log Exchange Web site. http://www.nplexservice.com/. Accessed October 19, 2013.
- Boards of Pharmacy, State Legislators, and Law Enforcement Continue to Tackle Methamphetamine Problem. National Association of Boards of Pharmacy Web site. http://www.nabp.net/news/boards-of-pharmacy-state- legislators-and-law-enforcement-continue-to-tackle-methamphetamine-problem. Access November 1, 2013
- Office of National Drug Control Policy: Fact Sheet: Methamphetamine Trends In the United States. The White House, Washington, Web site. http://www.whitehouse.gov/sites/default/files/ondcp/Fact_Sheets /pseudoephedrine_fact_sheet_7-16-10_0.pdf. Accessed October 5, 2013.
- Oklahoma State Board of Pharmacy: News. National Association of Boards of Pharmacy Web site. http://www.nabp.net/publications/assets/OK012011.pdf. Accessed October 9, 2013.
- ArkansasOnline. House passes bill on pharmacist-only pseudoephedrine. Arkansas Democrat-Gazette Web site. http://www.arkansasonline.com/news/2011/mar/16/house-passes-bill-pharmacist-only-pseudoephedrine/. Accessed October 3, 2013.
- Naclerio RM, Bachert C, Baraniuk JN. Pathophysiology of nasal congestion. Int J Gen Med. 2010;3:47-57.
- Eccles R. Substitution of phenylephrine for pseudoephedrine as a nasal decongestant. An illogical way to control methamphetamine abuse. Br J Clin Pharmacol. 2007;63(1):10-14.
- Ramey JT, Bailen E, Lockey RF. Rhinitis medicamentosa. J Investig Allergol Clin Immunol 2006;16(3):148-155.
- U.S. Food and Drug Administration (FDA). Nonprescription Drugs Advisory Committee Meeting: cold, cough, allergy, bronchodilator, antiasthmatic drug products for over-the-counter human use effectiveness and safety of phenylephrine hydrochloride and phenylephrine bitartrate as an oral nasal decongestant drug product, 2007. FDA Web site. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4335b1-04-FDA-vol1.pdf. Accessed November 14, 2015.
- Kollar C, Schneider H, Waksman J, Krusinska E. Meta-analysis of the efficacy of a single dose of phenylephrine 10 mg compared with placebo in adults with acute nasal congestion due to the common cold. Clin Ther. 2007;29(6):1057-1070.
- Horak F, Zieglmayer P, Zieglmayer R, et al. A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber. Ann Allergy Asthma Immunol. 2009;102(2):116-120.
- Taverner D, Danz C, Economos D. The effects of oral pseudoephedrine on nasal patency in the common cold: a double-blind single-dose placebo-controlled trial. Clin Otolaryngol Allied Sci. 1999;24(1):47-51.
- Eccles R, Jawad MS, Jawad SS, et al. Efficacy and safety of single and multiple doses of pseudoephedrine in the treatment of nasal congestion associated with common cold. Am J Rhinol. 2005;19(1):25-31.
- American College of Preventive Medicine (ACPM). Over-the-counter Medications: Use in General and Special Populations, Therapeutic Errors, Misuse, Storage and Disposal: A Resource from the American College of Preventive Medicine. ACPM Web site. http://c.ymcdn.com/sites/www.acpm.org/resource/ resmgr/timetools-files/otcmedsclinicalreference.pdf. Accessed October 12, 2013.
- U.S. Food and Drug Administration (FDA). Drug Applications for Over-the-Counter (OTC) Drugs. FDA Web site. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalAp plications/Over-the-CounterDrugs/default.htm. Accessed October 28, 2013.
- Zephrex-D [product information Web site]. Westport Pharmaeuticals, LLC Web site. http://zephrex-d.com/. Accessed October 1, 2013.
- Highland Pharmaceuticals, LLC. Tarex Extraction-Resistant Oral Drug Delivery System. Highland Pharmaceuticals, LLC Web site. http://www.highlandpharma.com/Assets/HP-PDFs/Tarex Fact Sheet 092712.pdf. Accessed November 5, 2013.
- Westport Pharmaceuticals, LLC. First & Only Pseudoephedrine Product to Stop “One Pot” METH Now in Pharmacies Nationally: Zephrex-D® with Unsurpassed Congestion Relief Not Found in METH Lab Seizures. Westport Pharmaceuticals, LLC Web site. http://zephrex-d.com/wp-content/uploads/2013/09/Zephrex-D-National-Launch-News-Release-09052013-FINAL.pdf. Accessed October 12, 2013.
- Acura Pharmaceuticals, Inc. Nexafed. Acura Pharmaceuticals, Inc. Web site. http://www.nexafed.com/. Accessed October 19, 2013.
- Schiff M. National Governors Association (NGA). The Role of Nurse Practitioners in Meeting Increasing Demand in Primary Care. 2012. National Governors Association Web site. http://www.nga.org/files/live/sites/NGA/files/pdf/1212NursePractitionersPaper.pdf. Accessed October 19, 2013.