continuing education

Abuse of OTC Drugs By Gerald Gianutsos, PhD, JD

pon successful completion of this abusing Rx and OTC drugs article, the pharmacist should be also abuse alcohol or other Useful Web Sites able to: drugs, and many combine ■ www.family.samhsa.gov/get/ 1. Describe the characteristics and their drug use with alco- otcdrugs.aspx significance of OTC drug abuse. hol, raising the potential of A Web site providing information to par- 2. Identify the signs of dextrometho- dangerous drug interactions ents on the dangers of OTC drugs. U rphan abuse. and other serious medical ■ www.mediacampaign.org/ 3. Explain the effects of , consequences. newsroom/press08/rx_rpt_2008.pdf pseudoephedrine, and antihistamines based Drugs from several An excellent, recent summary of govern- upon their pharmacodynamic properties. pharmacological classes ment information on Rx and OTC drug 4. Recognize the requirements for sales restric- have been subject to abuse abuse from the Office of National Drug tions on pseudoephedrine and prepare for by young people, including Control Policy. possible regulatory changes for other OTCs. cough and cold products, ■ www.deadiversion.usdoj.gov/drugs_ 5. Identify the populations at risk and the effects antihistamines, diet pills, concern/dextro_m/dextro_m.htm This site contains a review of the effects of laxative abuse. anabolic promoters, and and abuse of DXM. even laxatives. A survey of ■ www.fda.gov/fdac/features/2006/ INTRODUCTION pharmacists in Northern 406_meth.html When pharmacists think about drugs of abuse, Ireland revealed 112 different Link to article from the Food and Drug Ad- illicit street drugs such as heroin, marijuana, OTC products that pharma- ministration intended for the lay public on and cocaine would most likely be the ones to cists perceived were being the actions taken with pseudoephedrine. come to mind. Pharmacists are probably also abused, with a median of 10 ■ www.psychiatric-disorders.com/ aware of the growing epidemic of abuse of patients raising suspicion in articles/eating-disorders/anorexia/ prescription (Rx) drugs, especially opiate anal- a typical three-month period. anorexia-health-effects.php gesics. In fact, according to recent government (Note however that this Contains a discussion of the dangers of estimates, more young people between the survey included OTC opiates anorexia and the use of laxatives. ages of 12 and 17 abuse prescription drugs which are not generally avail- than any illicit drug except marijuana—more able in the United States, than cocaine, heroin, and methamphetamine and may overestimate the scope of the problem in the combined. United States.) In a survey of poison controls centers in However, the abuse of over-the-counter Utah over a 10-year period, more than one-third of the (OTC) drugs, especially by young people, is reported intentional drug abuse among adolescents also a significant problem that is not as well between 6 and 19 involved an OTC drug; 65 percent of appreciated. As these drugs are more read- the exposures occurred in the home and an additional ily obtainable, and are regarded by teens and 10 percent occurred in school. Some street-drug users parents as less risky than the controlled sub- also use OTC drugs as a secondary product when their stances, the abuse of OTC drugs has skyrock- regular drug of choice becomes unavailable or to boost eted and creates many problems that phar- the performance of their preferred drug. This lesson will macists need to address. Most young people review the non-medical use of some OTC substances,

www.americaspharmacist.net December 2008 | america’s Pharmacist 39 with an emphasis on the abuse of cough syrups con- formulations in an effort to reduce abuse by taining dextromethorphan (DXM) and cold products creating an unpleasant taste if ingested in containing pseudoephedrine (PSE). Recent regulatory large amounts. Among users, DXM is known efforts to curb the non-medical use of OTC drugs will to possess a bad taste and consumption of also be reviewed. large quantities of syrup, especially with guai- Although beyond the scope of this review, pharma- fenesin, is known to induce vomiting. cists also need to be aware of another emerging prob- nevertheless, intoxication with DXM- lem, the abuse of herbal products, some of which are containing products has become increasingly sold as dietary supplements or are available via the Inter- popular in the United States, particularly among net. Many of these products are promoted to teens and teens. The drug has profound psychological young adults as “safe, natural highs” and are usually less and physiological effects similar to those of rigorously regulated than traditional Rx or OTC drugs. phencyclidine (PCP), and its unrestricted ac- cess make it a prime target for abuse. DEXTROMETHORPHAN-CONTAINING According to the 2006 National Survey ANTI-TUSSIVES on Drug Use and Health conducted by the A woman enters the pharmacy with a concern about Substance Abuse and Mental Health Services her teenage son. He had been sent home from Administration (SAMHSA), about 3.1 million school after being found disoriented and slurring his young people between the ages of 12–25 had speech. There was no sign of alcohol on his breath. used an OTC cough and cold medication to After searching his room, she was relieved to find no get high, and nearly one million are estimated needles or bags of marijuana or other apparent illegal to have done so within the year preceding the substance. The son claimed he had a bad cold and survey. took some cough syrup which he had purchased at the frequency of use among adolescents the pharmacy and claimed to have had a “bad reac- is particularly high. Teenagers are the greatest tion.” She is questioning the pharmacist as to whether risk group for DXM abuse, with some likening this could have caused his behavior. What should the the effects to marijuana, but with a perceived pharmacist consider? lower risk of detection by parents, teachers, or other adults. The demographic group with Scope the largest percentage of misuse is Caucasian The mother in the scenario above has reason to be males, aged 18–25 (7.7 percent), although concerned. Abuse of cough syrups has become a abuse has been reported in children as young serious problem among young adolescents in the as nine. Surveys conducted on younger people United States. revealed strikingly high percentages of use; the cough suppressant dextromethorphan (DXM) four percent of 8th graders, five percent of 10th is the most popular antitussive in the United States and graders, and six percent of 12th graders had is found in more than 140 cough and cold medications abused OTC cough and cold remedies. Ac- available without a prescription. DXM was first approved cording to data obtained from poison centers, by the Food and Drug Administration for clinical use DXM abuse showed a 10-fold increase over in the United States in 1958 as an OTC alternative to the years 1999–2004, with a 15-fold increase codeine for cough. Initially marketed as a tablet un- among adolescents aged 9–17 years, with der the trade name Romilar, the drug was diverted to the number of children in the 12–14 year old recreational use and case reports of DXM abuse have group approaching that of older teens. Most surfaced since the 1960s in the United States, Canada, people in the 12–25 year-old group who used and Europe. Ultimately Romilar was removed from OTC cold and cough remedies to get high the market in 1973. Shortly after its removal, pharma- in the past year also used alcohol and illicit ceutical companies reintroduced the drug in liquid drugs. The lifetime prevalence of DXM abuse in

40 america’s Pharmacist | December 2008 www.americaspharmacist.net one sample of 11th- and 12th-grade students “skittles” or “Red Hots” because of their resemblance to in Ohio was higher than the use of anabolic the popular candy. Users call the habit of misusing solid steroids, methamphetamine, heroin, crack, and dosage forms as “Skittling.” Some other street terms for methylphenidate. Alarmingly, fewer than half of DXM include Orange Crush, Vitamin D, and Robo. One teens believed that abusing cough medicine to particularly popular form of DXM is the product Coricidin, get high is risky. a mixture of 30 mg dextromethorphan hydrobromide and Even if the user is found with a supply of 4 mg chlorpheniramine maleate per tablet. Users refer the drug, it would be easy to mislead a par- to this preparation as “Triple C’s” (Coricidin Cough and ent, teacher or law enforcement agent, as the Cold Tablets). According to at least one survey, as many user would be carrying a seemingly innocuous as 87 percent of dextromethorphan abuse cases re- cold remedy and could readily explain away ported to poison control centers involved Coricidin HBP its presence. Moreover, parents feel that Rx (67 percent) or another Coricidin product (21 percent), and OTC drugs are safer than street drugs if highlighting the prevalence of this particular product. The abused and teens believe that parents don’t manufacturer (Schering-Plough) maintains a Web site care as much if they are caught with an Rx/ which contains information on abuse and tips for par- OTC drug. According to recent surveys, about ents (www.coricidin.com/InformationOnAbuse/Default. 70 percent of parents discussed the risks of htm). In another survey of persons aged 12– 25 who marijuana “a lot” with their children, but only 36 had misused an OTC cough and cold medication in the percent reported doing the same with pre- past year, 30.5 percent misused a NyQuil product, 18.1 scription drugs, and only 33 percent with OTC percent misused a Coricidin product, and 17.8 percent cough or cold medications. misused a Robitussin product. These statistics illustrate others teens cited the ease with which that pharmacists need to be vigilant when observing OTC drugs could be obtained, which does not young people purchasing or browsing these types of require contact with a dealer or other unsavory products and should be prepared to take appropriate environment, but merely necessitates going to steps when warranted. a pharmacy or local convenience store. The ad- Many Web sites can be found providing recipes for vent of automated checkout in many stores fur- the extraction of DXM from cough and cold products. ther reduces the probability of detection. Many Essentially, the drug is converted to the free base us- youths also admitted to stealing the products ing a base, typically NaOH or ammonia, which is then off pharmacy shelves; this activity has become extracted using methanol or lighter fluid/naphtha. The so common that many pharmacies have moved organic liquid is evaporated and the DXM is ingested. DXM products behind the counter to prevent Alternatively, the DXM is extracted from the organic solu- diversion. tion using lemon juice to make a lemon flavored liquid or solid dosage form. These procedures not only provide a Pattern of Use more concentrated form of DXM but also lessen the po- Adolescent DXM abusers intoxicate themselves tential for vomiting during intake. Powdered DXM is also at parties and before or after school, as the available on the street in a concentrated form. The FDA drug is legal, relatively inexpensive, and easily reported in the death of at least five teenagers in 2005 obtainable. DXM is available in different formu- from ingestion of powdered DXM. DXM is also some- lations, including solid and liquid dosage forms. times found in illicitly distributed tablets mixed with other Many users drink large quantities of cough illegal drugs such as ecstasy and/or methamphetamine, syrup in an effort to get high, but these efforts and is sometimes mixed with street heroin to increase the are minimized by the disagreeable taste and pharmacologic effects. susceptibility to vomiting. Solid dosage forms facilitate abuse. Effects of DXM DXM gelcaps are colloquially referred to as Most users of DXM describe profound psychological

www.americaspharmacist.net December 2008 | america’s Pharmacist 41 Table 1: Effects of Dextromethorphan anxiety, depression, restlessness, and intense cravings, although physical dependence has • Increased perceptual awareness • Altered time perception not been reported. • Feelings of floating and dissociation from the body Some non-psychological effects of DXM • Tactile, visual, or auditory hallucinations include: sweating, hot flashes, ataxia, nystag- • Visual disturbances mus, nausea and dizziness, diarrhea, severe •Paranoia weight loss, tachycardia, hypertension, rashes, • Disorientation and lack of coordination itching, and red blotchy skin. • Slurred speech • Impaired judgment and mental performance DXM Toxicity The more serious adverse effects of abusing large doses of DXM include hyperexcitability effects after consumption consisting of acute euphoria and seizures, increased muscle tone, and followed by intense craving and dysphoria on withdrawal. ataxia. Hyperthermia may reach dangerous Some of the psychological effects noted after acute in- levels and should be managed aggressively. toxication include perceptual, cognitive and motor altera- Recent guidelines recommend that patients tions, and are summarized in Table 1 (above). who have ingested more than 7.5 mg DXM/kg intoxicated users often exhibit a distinctive, plod- should be referred to an emergency depart- ding ataxic gait that has been likened to “zombie-like” ment for evaluation. Death from DXM over- walking. Severely intoxicated individuals may become dose is rare as the usual method of ingestion agitated or stuporous. Experienced users describe the induces vomiting. Most deaths result from effects of DXM as four dose-dependent “plateaus.” (See ingesting the drug in combination with other il- Table 2, below.) Note that the normal dose for cough legal drugs, alcohol, or other ingredients in the suppression is 15–30 mg; the plateaus described by us- mixtures. DXM-related deaths also occur from ers represent a dose 3–100 fold higher than the normal impairment of the senses, which can lead to therapeutic dose. accidents. Anecdotal reports suggest the pos- Anecdotal reports suggest a divergent experience sibility of brain damage from very high dose among first time users of DXM with only one-third of and chronic use. those who initially experimented with the drug report- As DXM abuse rises, the incidence of seri- ing that they liked it. A toxic psychosis has been re- ous adverse consequences also increases. ported following chronic use of the drug, characterized Calls to poison control centers involving abuse by a loss of contact with reality, a confused state, and or misuse of DXM increased 21 percent overall cognitive deterioration. Some users also exhibit violent from 2000 through 2002, but calls involving behavior, which is also characteristic of PCP abuse. teenagers increased approximately 100 per- Experienced users describe a rapidly developing and cent from 2000 (1,623) through 2003 (3,271). persistent tolerance to DXM. The primary symptoms Another study of cases involving ingestion of a observed during withdrawal are insomnia, dysphoria, dextromethorphan-containing product recorded

Table 2: Effects of DXM as a Function of Dose Plateau Dose (mg) Behavioral Effects 1st 100–200 Mild stimulation

2nd 200–400 Euphoria and hallucinations

3rd 300–600 Distorted visual perceptions Loss of motor coordination 4th 500–1500 sedation

42 america’s Pharmacist | December 2008 www.americaspharmacist.net at a poison control center revealed that in the instability, and increased muscle tone. DXM can also instances where the reason for the adverse re- potentiate the dangerous hyperthermia produced by action was known, 86 percent were associated MDMA (Ecstasy). with intentional abuse and 89 percent of these treatment of acute DXM intoxication is mainly sup- were patients 13–17 years old, with one patient portive. Some patients may be severely agitated and being only 11. require physical restraint. The agitation may be controlled Abuse of DXM as the common hydrobro- with benzodiazepines. Benzodiazepine sedatives can mide salt can also lead to signs of bromism in also help control seizures and may also reduce associ- heavy users. Typical signs of bromide toxicity in- ated hypertension and tachycardia. Activated charcoal is clude impaired CNS function including behavior- used in cases of recent intoxication (less than one hour al changes, headache, apathy, irritation, slurred following ingestion), but is of unclear benefit. Respiratory speech, psychosis, tremulousness, ataxia, hallu- depression and coma have been reported in rare cases cinations, and the possibility of coma. However, and may respond to high IV doses of naloxone. If anti- acute bromide toxicity is believed to be relatively cholinergic signs are present, especially if a combination rare, as ingestion of large amounts of bromide product containing an antihistamine has been ingested, typically causes vomiting, which limits gastroin- physostigmine may be considered. testinal bromide absorption. Another problem associated with abuse of Pharmacology DXM-containing cough syrup is the potential DXM is the dextro isomer of levomethorphan, an opiate toxicity from other active ingredients found in and the methyl ether analog of levorphanol the mixtures. These may include overdose of (Levo-Dromoran). However, DXM does not have affin- antihistamines, sympathomimetic deconges- ity for the opiate receptors. Instead, DXM and its active tants, , and acetaminophen when metabolite, dextrorphan, act as potent blockers of the large amounts of cough and cold preparations N-methyl -D-aspartate (NMDA) receptor, a member of are ingested. Antihistamines can produce the family of receptors for the excitatory neurotransmit- anticholinergic signs and symptoms (such as ter, glutamate. At high doses, the pharmacology of DXM tachycardia, warm, dry, flushed skin, dry mouth, is similar to the controlled substance phencyclidine mydriasis, agitated delirium, urinary retention, (PCP; angel dust) and the veterinary anesthetic ket- and decreased gastrointestinal mobility). Se- amine, drugs that also antagonize the NMDA receptor. vere intoxication has also been associated with The similarity in their mechanism of action accounts for seizure activity and hyperthermia. Deconges- the PCP-like behavioral effects produced by high doses tants may produce cardiovascular complica- of DXM. The metabolite, dextrorphan, has a higher affin- tions, including hypertension and tachycardia, ity for the NMDA receptor than does the parent com- while acetaminophen overdose is associated pound and is comparable to ketamine. DXM may cause with liver and kidney damage. a false-positive test result with some urine immunoas- one well characterized drug interaction says for PCP. with DXM is the development of a serotonin DXM also acts on Sigma receptors, which are be- syndrome. This condition typically occurs from lieved to account for the anti-tussive activity, and also the interaction between DXM and selective interacts with serotonergic neuronal systems. serotonin reuptake inhibitors or monoamine oxidase inhibitors. Some antibiotics (such as Pharmacokinetics linezolid), opiate (such as meperi- DXM is well absorbed following oral ingestion. The half- dine and tramadol), or drugs of abuse can life of the parent compound is approximately two to four also precipitate the condition. Patients with hours in individuals with normal metabolism. Effects gen- serotonin syndrome may demonstrate the clini- erally last for six hours, but may vary depending on the cal triad of mental status changes, autonomic amount of DXM ingested, and if it is used in combination

www.americaspharmacist.net December 2008 | america’s Pharmacist 43 with other drugs. Dextromethorphan and its metabolites introduced in Congress in 2007 (the Dextro- undergo renal elimination. methorphan Abuse Reduction Act) which, if Dextromethorphan undergoes metabolism via passed, would place raw DXM in Schedule V Cytochrome P450 CYP2D6. DXM is 3-demethylated to and would restrict the sale of DXM-containing dextrorphan and, to a lesser extent, N-demethylated cough and cold products to consumers over to 3-methoxymorphinan; both metabolites are further 18. Significant for pharmacists, the legislation demethylated to 3-hydroxymorphinan. Dextrorphan is would make it illegal to knowingly sell DXM- an active metabolite that prolongs the central nervous containing products to individuals under 18 system effects of DXM. CYP2D6 is involved in the oxida- years old, and would impose civil penalties of tion of a wide variety of drug substrates including opiates, up to $1,000 for a first violation, up to $2,000 most antidepressants and antipsychotics, and many for a second violation, and $5,000 for a third anti-arrythmics, but there is a wide phenotypical variability violation for retailers who do so. Retailers among individuals with most of the U.S. population being failing to check a government-issued identi- rapid metabolizers. However, approximately 5 percent to fication for an individual under 18 years old 10 percent of Caucasians are poor DXM metabolizers, would be deemed to have knowledge that the which increases their risk for overdose and death. Slow person was underage and would be subject metabolizers show greater psychomotor impairment and to the penalties; however, the bill provides an sedation. However, slow metabolizers also exhibit less affirmative defense for retailers who check euphoria and greater dysphoria, due to a decrease in identification and reasonably believe it to formation of dextrorphan, and may be less likely to abuse prove that the purchaser is over 18. DXM. Experienced dextromethorphan users describe a Some states are also considering putting tachyphylaxis to the drug, but it is unknown whether this age restrictions on DXM sales, while some par- effect is due to alterations in metabolic activity or some ent groups believe that DXM, because it’s so ac- other effect. cessible, is a bigger problem than other drugs and support taking it off drug store shelves. Regulatory Issues Consequently, regulatory changes governing A teenager walks up to the pharmacy counter with 12 DXM is a very real possibility. bottles of cough syrup-DM. The pharmacist questions in many states, pharmacies are already the young man, who tells him that he and his two broth- voluntarily refusing to sell DXM-containing ers have a bad cough and his mother sent him to the products to anyone under 18 and/or are limiting pharmacy for the medicine. Should the pharmacist take the amount that can be purchased at one time. any action? Wal-Mart’s policy is to sell it only to customers DXM is not a controlled substance under the Con- 18 or older, and the chain limits the number of trolled Substances Act (CSA). The CSA specifically boxes people can buy to three. excluded DXM from any of the schedules when it was en- in the 1980s, an epidemic of adolescent acted in 1970 because of a lack of significant opiate-like and teenage abuse of DXM in Utah resulted abuse potential despite its structural similarity to opiate in the voluntary removal of the drug from drugs. The Drug Enforcement Administration is currently store shelves to behind pharmacy counters. reviewing DXM for possible control, possibly adding it to This measure has resurfaced as a potential Schedule IV or V. solution, but manufacturers are opposed Should the DEA decide to further regulate DXM, to this idea, claiming that putting it behind some other possible regulatory strategies they could the counter would deprive those who need use for cough products are restricted access, limits on it. Instead, they propose improved warning amounts sold, age restrictions, and the use of a log labels and changing the packaging so that it book similar to Schedule V controlled substances or is harder to shoplift. the recent changes with pseudoephedrine. A bill was in 1986, the Swedish National Board of

44 america’s Pharmacist | December 2008 www.americaspharmacist.net Health and Welfare changed DXM to prescrip- natural product regulated by the Dietary Supplement and tion drug status because of teenage abuse Health Education Act (DSHEA), ephedrine proved to be of the product. Illinois passed a law in 2006 more difficult for the FDA to remove. classifying pure DXM as a Schedule II drug; sale of DXM in this form, including over the In- Pseudoephedrine ternet, is punishable by three to seven years in Another substance still commonly found in OTC cold prison. Similar legislation has been considered remedies, pseudoephedrine (PSE), has also been as- in other states. including Texas, North Dakota, sociated with a serious public health problem. However, and California. with PSE, the problem is not with the consumption of the parent compound but instead with the illicit manufactur- OTC DECONGESTANTS ing of methamphetamine, using PSE as a precursor. Other ingredients in OTC cold preparations Formulas for converting PSE to methamphetamine can have also been the subject of abuse. The be found on numerous Web sites and much of the meth- abuse of OTC sympathomimetic deconges- amphetamine available in the United States is manufac- tants has long been recognized as a prob- tured in small, portable home-based labs, starting with lem due to their amphetamine-like stimulant PSE obtained from OTC products, preferably from single effects. Over the past few decades, the most ingredient tablets. commonly available over-the-counter decon- Methamphetamine is a widely abused stimulant gestants have been ephedrine, phenylpropa- drug which produces a brief, intense sensation, or nolamine (PPA), pseudoephedrine and phenyl- rush, in those who smoke or inject it. The rush or ephrine. Ephedrine and PPA were also found in “flash” lasts only a few minutes and is described as OTC weight reduction products and were used extremely pleasurable. Oral ingestion or snorting differs to enhance athletic performance. Typically, de- by producing a long-lasting euphoric high instead of congestants act by activation of postjunctional a rush, which reportedly can continue for a half day. alpha adrenergic receptors in pre-capillary and Some identifiable features of methamphetamine abus- post-capillary blood vessels of the nasal mu- ers include agitation, excited speech, decreased appe- cosa, producing vasoconstriction, resulting in tite, and increased physical activity levels. In addition to a decrease in blood flow through the mucosa its CNS effects, methamphetamine can cause a variety and shrinkage of the tissue. Decongestants of cardiovascular problems, including rapid heart rate, may act directly on the alpha receptor or indi- irregular heartbeat, increased blood pressure, and rectly by increasing the pre-junctional release irreversible stroke associated damage to small blood of norepinephrine from sympathetic neurons vessels in the brain. Other common features include and this action also contributes to their stimu- dilated pupils, shortness of breath, nausea, vomiting, lant properties. diarrhea, and elevated body temperature. Hyperther- PPA was the subject of an FDA voluntary mia and convulsions can also occur with metham- recall in 2000, due to evidence of an increased phetamine overdoses, and if not treated immediately, risk of hemorrhagic stroke, especially in women can result in death. In addition, research in laboratory and its use in OTC products was banned by the animals suggests that methamphetamine can irrevers- FDA in 2006. ibly damage brain cells. Ephedrine is a naturally occurring alkaloid Along with the health issues associated with the derived from the Ephedra plant which shares abuse, small scale methamphetamine manufactur- pharmacological properties with other decon- ing also results in other important public health and gestants. Ephedrine was banned by the FDA safety problems, including a high risk of child abuse in 2004 after a lengthy regulatory dispute, and neglect, criminal activity in the community, risk because of the risk of producing hypertension of fires and environmental contamination due to the and stroke, including at least 10 deaths. As a prevalence of large volumes of solvents used in the

www.americaspharmacist.net December 2008 | america’s Pharmacist 45 manufacturing process, and the added toxicity from the small scale domestic production of metham- IV administration of relatively impure and poorly manu- phetamine, according to the Bureau of Interna- factured products. tional Narcotics and Law Enforcement Affairs, in an effort to reduce the clandestine manufacture although the production has shifted to larger of methamphetamine, the Combat Methamphetamine labs in Mexico. As mentioned earlier, similar Epidemic Act was enacted in 2006. This act modified restrictions on retail sales have been recom- several previous laws going back almost two decades mended by regulatory and consumer groups and placed a number of now familiar restrictions on the for DXM and the prudent pharmacist should sale of PSE. Among the provisions of the act are require- stay abreast of changes in federal, state and ments that each regulated seller (such as a pharmacy) local laws regulating sales of DXM. Pharma- ensure that: cists may also wish to follow the lead of other • Customers do not have direct access to the product pharmacies and place DXM-containing prod- before the sale is made, meaning that products must be ucts behind the counter, especially if shoplifting placed in a secure location not ordinarily accessible by has become a problem. the general public. Most pharmacies place them behind the prescription counter, but this is not a requirement. L-desoxyephedrine • A printed or electronic logbook listing sales is kept. L-desoxyephedrine (Vicks Inhaler) is also • The amount that can be purchased in a single day and known by its newer name, levmetamfetamine. in a month is limited. This is the optical isomer of methamphet- amine and is about one quarter the potency under the revised 2006 law, retail sales may not of the more active d-enantiomer. Abuse of exceed 3.6g PSE base per day per purchaser, regardless levmetamfetamine-containing products, of the number of transactions. The previous law placed known colloquially as “peanut butter metham- limits only on individual transactions. Moreover, individual phetamine” used to be quite common, but the consumers are prohibited from purchasing more than 9g increased availability of authentic metham- PSE per 30-day period. phetamine has reduced its desirability. Abuse the logbook for retail PSE purchases must contain the ordinarily involves opening the inhaler, extract- following information for each sale: ing, and then injecting the drug or, alterna- • Purchaser’s name and address tively, swallowing the cotton inside. A similar • Date and time of sale practice is also followed for propylhexedrine, • Name of product sold the active constituent of the Benzedrex inhaler. • Quantity sold Internet resources purport to provide methods • Purchaser’s signature to synthesize d-methamphetamine from the inhalers. the retailer is obligated to enter the name of the product and quantity sold and to check information Substituted Piperazines entered by the purchaser against a photo identifica- While they are not used as decongestants, tion. The photo ID must be one issued by a state or the substituted piperazines (such as N-benzylpi- federal government, a passport, or an alien registration perazine [BZP] and trifluoromethylphenylpiper- receipt card or permanent resident card (“green card”). azine [TFMPP]) produce a stimulant, euphoric Each record must be retained for a period of two years effect similar to methylenedioxymethamphet- after entry. The act exempts the requirements of a log- amine (MDMA, “Ecstasy”). Although these book for any purchase by an individual of a single sales products are illegal in the United States (BZP is package if that package contains not more than 60 mg a Schedule I drug) they can be purchased OTC of pseudoephedrine (such as one or two dose units). in Canada, New Zealand, the United Kingdom, the enhanced controls have successfully reduced and other countries, where they are known as

46 america’s Pharmacist | December 2008 www.americaspharmacist.net “herbal party pills” and can be purchased over “T’s and Blues”) for decades to produce a concoction the Internet as a “natural” substitute for Ecsta- indistinguishable from heroin, and antihistamines have cy. (Although synthetic, they are referred to as also substituted for LSD in experienced users. Because herbals because of an erroneous association of the risk of widespread abuse, some experts have with the pepper plant.) Reported side effects proposed restricting sales of some antihistamines, just include insomnia, anxiety, nausea, vomiting, as sales of PSE cold medicines have been limited. hyperthermia, cardiac arrhythmias, tachycar- dia, abdominal pain, acute renal failure, acute LAXATIVES AND EMETICS psychosis, and seizures. One form of pipera- Laxatives and emetics are abused under a number of zine that is found in the United States is known different circumstances. Unlike the previously dis- colloquially as “rapture.” cussed drugs which are abused for their euphoric CNS effects, laxative and emetic abusers are looking for ANTIHISTAMINES a different benefit. These drugs are abused by indi- Although less prevalent than DXM abuse, viduals who mistakenly believe that they will prevent antihistamines are known to be abused as the absorption of calories from ingested food and by a source of a cheap, readily available high individuals who believe that daily bowel evacuation among adolescents since at least the early will promote good health. However, one of the more 1970s. The drugs are abused for their halluci- serious concerns is the frequent abuse of laxatives and nogenic effects and to obtain a sense of eu- emetics in patients with anorexia and bulimia nervosa. phoria. Usually, very high doses (such as more In one survey of patients seeking treatment for eating than 400 mg of dimenhydrinate) are used in an disorders, more than 25 percent had abused a laxative effort to produce the high. The antihistamines in the preceding three months. The laxative misus- can produce a toxic psychosis resembling ers scored significantly higher than non-misusers on atropine delirium consisting of visual and audi- measures of anorexic behaviors and weight and shape tory hallucinations; this is not unexpected since concerns and also displayed higher levels of depres- the most commonly abused anti-histaminic sion and self-directed hostility. drugs possess anti-muscarinic properties. Ini- Similarly, laxative abuse in patients with eating tially the effects consist of euphoria, and later disorders has been associated with longer duration of disorientation, ataxia, and visual hallucinations. illness, suicide attempts, impulsivity, and greater eating The toxicity from the high doses of antihista- and general psychopathology. Individuals who misused mines has been misdiagnosed as a psychiatric laxatives were older, were perceived to be in poorer disorder. Other antimuscarinic signs accompa- physical health, and were less likely to have sought nying the misuse include tachycardia, mydria- treatment specifically for an eating problem than those sis, hot flushed dry skin, dry mouth, and mild who engaged in self-induced vomiting. The abuse of hypertension. laxatives as well as OTC diuretics is also becoming the most commonly reported abused an- more common in female athletes, particularly those tihistamines are diphenhydramine (Benadryl), starting in competitive activities at a young age or those dimenhydrinate (Dramamine), and meclizine who are engaged in activities such as gymnastics, figure (Bonine), but any depressant, sedating anti- skating, and ballet, where weight and body image are a histamine (such as one which penetrates into factor. Data on emetic abuse among patients with eating the CNS) is potentially susceptible to abuse. disorders also suggests that this is a cause for con- Antihistamine abuse is especially common cern. Studies investigating the extent of ipecac abuse in individuals with a history of drug abuse in patients with eating disorders report that as many as and in individuals with a history of psychiatric 7.8 percent of patients had used ipecac, 3.1 percent disorders. Experienced drug users have used using the drug chronically. Anecdotal reports suggest antihistamines with pentazocine (such as that some women with eating disorders may take as

www.americaspharmacist.net December 2008 | america’s Pharmacist 47 much as four bottles of ipecac per day. Laxative and going beyond those described in this lesson, emetic abuse have also been reported as a factor in reinforces the importance that pharmacists Munchausen syndrome by proxy. need to place on OTC drugs when taking drug the abuse of stimulant laxatives and emetics may histories and during counseling sessions. lead to a number of metabolic and gastrointestinal complications including diarrhea with associated sodium and water loss and dehydration; potassium Gerald Gianutsos, BS Pharm, MS, PhD, JD is an associate loss and hypokalemia, the potential for hypocalcaemia professor of pharmacology at the University of Connecticut and hypomagnesaemia resulting in tetany, acid-base School of Pharmacy, Storrs, Connecticut. disturbances; and renal damage. Cardiac and muscle toxicity and cardiac arrest have also been reported. Abuse of emetics was reportedly a major factor in the death of singer Karen Carpenter, who suffered from anorexia. Incidents such as these have prompted the Editor’s Note: To obtain the complete list of refer- call for a ban on the sale of ipecac and restrictions on ences used in the article, contact Chris Linville laxative sales. In 2003, an FDA advisory panel voted to at NCPA (703-838-2680), or at chris.linville@ rescind OTC sales of ipecac. ncpanet.org.

SUMMARY AND CONCLUSIONS The abuse of OTC drugs is not a new problem but is one that has, along with prescription drug abuse, taken on new importance, especially among the adolescent population. The ease of obtaining the drugs, the low risk of detection, and the relatively poor perception of the risks involved by both teens and parents has contributed to the explosion in the abuse of OTC drugs, which shows no signs of abating. This presentation highlighted the abuse of dextromethoro- phan, which produces PCP-like effects and the abuse of stimulant OTC decongestants, which substitute for amphetamines. But, interested individuals are able to identify other drugs for possible abuse and the exis- tence of the Internet permits rapid dissemination of information to other potential users. Pharmacists are familiar with the restrictions placed on pseudoephedrine-containing products in an effort to reduce their diversion, and the possibility exists that similar limitations may be placed on dextromethorphan and potentially other drugs as well. At the very least, pharmacists need to be aware of requests for exces- sive quantities of OTC drugs, especially by adoles- cents and by patients with a history of drug abuse or psychiatric illness. Pharmacists should also consider voluntary measures such as keeping certain products out of sight. the abuse and misuse of a long list of OTC drugs,

48 america’s Pharmacist | December 2008 www.americaspharmacist.net

CONTINUING EDUCATION QUIZ 5. The subjective effects of dextromethorphan most Select the correct answer. closely resemble which drug of abuse? 1. The abuse of prescription and OTC drugs: a. Heroin a. Is a problem but lags far behind the use of b. Phencyclidine (PCP) most street drugs c. Methamphetamine b. Is rarely associated with alcohol abuse d. Cocaine c. Is a problem restricted to the United States d. Often occurs in the home or school 6. The term “skittling” refers to: a. The use of OTC drugs of abuse at parties where candy 2. The abuse of dextromethorphan: is also served a. Exceeds the abuse of methamphetamine b. The abuse of dextromethorphan in solid dosage forms among 12th graders that resemble popular candy b. Remained constant from 1999-2004 c. Adding candy to cough syrup to mask the taste c. Is especially frequent in liquid forms because d. The abuse of cough syrup by very young adolescents of the pleasant taste d. Is a problem among high school students but 7. The usual dose of dextromethorphan for treating is not seen in younger children coughs is: a. 15–30 mg 3. The demographic with the highest misuse of b. 50–75 mg dextromethorphan is: c. 100–150 mg a. African American males, aged 18-25 d. 500–1,000 mg b. Caucasian males, aged 18–25 c. Caucasian females, aged 18–25 8. Experienced dextromethorphan users refer to drug d. Caucasian males, aged 14–17 plateaus. Which statement is correct? a. The first plateau (i.e., lowest dose) describes effects at 4. Abuse ofOTC cough products is growing more than 25 times the usual therapeutic dose because: b. Dissociative sedation occurs at plateau four a. Parents are less concerned about non-street c. Effect occurring at first plateau is visual distortions drugs. d. Euphoria requires a dose of 1,000 mg or more. b. Teenagers do not appreciate the risks associ- ated with abuse of OTC drugs. 9. The active metabolite of dextromethorphan is: c. The products are relatively easy to obtain from a. Levomethorphan pharmacies. b. Dextrorphan d. All of the above are correct. c. Ketamine d. The metabolites are all pharmacologically inactive

www.americaspharmacist.net December 2008 | america’s Pharmacist 49

10. The metabolism of dextromethorphan: 15. Sales of pseudoephedrine have been regu- a. Occurs primarily via CYP3A4 lated because: b. Is slow, resulting in a half life of more than 18 hours a. There is a high risk of cardiovascular compli- c. Is slower than normal in approximately 5-10 percent of cations. Caucasian users b. It is highly abused for its CNS effects. d. All of the above are correct. c. It is used in the illicit manufacture of metham- phetamine. 11. Toxicity from an overdose of dextromethorphan d. It is frequently used as a substitute for heroin. includes: a. Hyperexcitability and seizures 16. Agitation and excited speech are character- b. Fall in body temperature istic signs of the abuse of: c. Hypotension a. Dextromethorphan d. A contraindication to the use of benzodiazepines b. Anti-histamines c. Heroin 12. Other types of toxicity associated with the abuse d. Methamphetamine of dextromethorphan-containing cough products include: a. Liver damage due to acetaminophen 17. Log books for sales of pseudoephedrine b. Hypertension and tachycardia from decongestants require the recording of the following information c. Possible signs of bromide toxicity except: d. All of the above are correct. a. The purchaser’s names b. The purchaser’s address 13. The proposed Dextromethorphan Abuse Reduction c. The purchaser’s driver’s license or alien regis- Act would change the regulation of dextromethorphan by: tration ID number a. Reclassifying it as a Schedule II drug d. The amount purchased and the date b. Restricting sales of dextromethorphan containing cough syrups to consumers age 18 or older 18. Abuse of levmetamfetamine inhalers: c. Placing cough syrups behind the counter a. Is rarely a problem because the drug is d. Banning the sale of cough products containing dextro- found in a wad of cotton from which methorphan as the sole ingredient extraction is difficult b. Is a problem which is becoming 14. Phenylpropanolamine and ephedrine were removed more common from the market because of: c. Produces effects similar to methamphetamine a. Poor efficacy d. Is not a problem because the drug does not b. Excess CNS stimulation produce effects on the CNS c. Risk of stroke d. Kidney toxicity

50 america’s Pharmacist | DecemberAugust 2008 2008 www.americaspharmacist.net

19. Which of the following effects may be asso- Abuse of OTC Drugs ciated with the abuse of antihistamines? Dec. 1, 2008 (expires Dec. 1, 2011) a. Disorientation and ataxia FREE ONLINE CE Pharmacists now have online access to NCPA’s CE b. Visual hallucinations programs through Powered by CECity. By taking this test online—go to the Continuing Education section of the NCPA Web site (www.ncpanet. c. Delirium org) by clicking on “Professional Development” under the Education d. All of the above heading you will receive immediate online test results and certificates of completion at no charge.

20. The signs of antihistamine abuse most To earn continuing education credit: ACPE Program 207-000-08-012-H01-P closely resemble an overdose of: A score of 70 percent is required to successfully complete the CE quiz. a. Methamphetamine If a passing score is not achieved, one free reexamination is permitted. Statements of credit for mail-in exams will be available online for you b. An anti-muscarinic to print out approximately three weeks after the date of the program c. Heroin (transcript Web site: www.cecerts.ORG). If you do not have access to a d. LSD computer, check this box and we will make other arrangements to send you a statement of credit: q

Record your quiz answers and the following information on this form. q NCPA Member License NCPA Member No. ______State ______no. ______q Nonmember State ______no. ______

All fields below are required. Mail this form and $7 for manual processing to: NCPA CE Processing Ctr.; 405 Glenn Drive, Suite 4; Sterling, VA. 20164 ______Last 4 digits of SSN MM-DD of birth ______Name ______Pharmacy name ______Address ______City State ZIP ______Phone number (store or home) ______Store e-mail (if avail.) Date quiz taken

Quiz: Shade in your choice a b c d e a b c d e 1. q q q q q 11. q q q q q 2. q q q q q 12. q q q q q 3. q q q q q 13. q q q q q 4. q q q q q 14. q q q q q 5. q q q q q 15. q q q q q

6. q q q q q 16. q q q q q 7. q q q q q 17. q q q q q 8. q q q q q 18. q q q q q 9. q q q q q 19. q q q q q 10. q q q q q 20. q q q q q

Quiz: Circle your choice 21. Is this program used to meet your mandatory CE requirements? a. yes b. no 22. Type of pharmacist: a. owner b. manager c. employee 23. Age group: a. 21–30 b. 31–40 c. 41–50 d. 51–60 e. Over 60 24. Did this article achieve its stated objectives? a. yes b. no 25. How much of this program can you apply in practice? a. all b. some c. very little d. none

How long did it take you to complete both the reading and the quiz? ______minutes

NCPA® is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCPA has assigned two contact hours (0.2 CEU) of continuing education credit to this article. Eligibility to receive continuing education www.americaspharmacist.net credit for this article expiresAugust three years 2008 from |the america’s month published. Pharmacist 51