Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements (2011)

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

27 INTRODUCTION TO STIMULANTS AND ALERTNESS-ENHANCING COMPOUNDS Many commercial drivers put in long hours of driving on a daily basis (11 h permitted out of a 14-h work day). Their situation presents a particularly acute safety concern in that they might develop driver fatigue during long drives common in over-the-road operations. Drivers in short-haul operations may alternate lengthy duty periods, waiting to pick up or deliver loads locally, or make multiple revenue run deliveries stretching their duty day. In this synthesis the safety concern turns attention to the possibility of some commercial drivers using wake-promoting compounds (stimulants) in their attempts to maintain alertness and to sustain or enhance driving performance. Discussion focuses on stimulating and wake-promoting compounds often mentioned in the com- mercial driving community and devotes special attention to the effects on driving safety. Caveat. A word of caution, although some of the advantages and disadvantages of medical management of prescription stimulant use are described, it is not the intent to suggest that stimulants of any type can be a replacement for commercial drivers adhering to a personal good sleep management program. Obtaining a sufficient quantity of quality sleep on a daily basis is the most conducive way to maintain alertness and to manage driver fatigue. Sleep also is an important key to maintaining overall good health (Krueger 1989; Krueger et al. 2007a, b). STIMULANTS AND ALERTNESS-ENHANCING COMPOUNDS A variety of “wake-promoting” chemical compounds, referred to as stimulants, include not only those in the Schedule II drug category, such as amphetamine-like compounds, but also include the two most common and less threatening stimulants: caffeine and nicotine. Some stimulant drugs have a role in the clinical treatment of conditions such as excessive sleepiness attributable to sleep disorders (e.g., narcolepsy), ADHD, and depression (Mitler and O’Malley 2005; Kay et al. 2009). Because their pharmacologic profiles are diverse, clinicians guide the selection of stimulating agents based on a variety of factors, including time of onset, length of activity, degree of tolerance in chronic use, side effects expected, abuse liability, and, importantly, a knowledge of whether and how the use of such medication might affect a person’s job performance. Wake-promoting medications fall into three chemical classes: (1) direct-acting sympathomimetics, such as the alpha-adrenergic agonist phenylephrine; (2) indirect-acting sympathomimetics, such as amphetamines, methylpheni- date (e.g., Ritalin®), mazindol, and pemoline; and (3) the “non- stimulants” that are not sympathomimetics, which have different mechanisms of action, such as modafinil and caffeine (Mitler and O’Malley 2005). The pharmacology of sympatho- mimetics is reviewed by Nishino and Mignot (2005). Prescription Stimulants and Amphetamines Introduction The most potent stimulant of natural origin, cocaine, has medicinal uses; however, for the most part, its current use is illicit. Research literature on cocaine and on marijuana (cannabis, another substance illegal in many jurisdictions) and their effects on driving performance are briefly described together in Appendix A to this synthesis report. Legitimate pre- scription stimulants include amphetamines, methylphenidate, and others. Although there is a vast literature documenting research on most stimulants, the concern here is to describe those stimulants that hold some potential for practical use as alertness-enhancing compounds in transportation operations. For interested readers, a considerable number of such literature citations involving research on stimulants and performance are listed in the web-only Appendix E (Bibliography). Amphetamine, Dextroamphetamine, and Methamphetamine Amphetamines and related compounds may be prescribed to treat some medical conditions. Medical uses for amphetamines include the treatment of narcolepsy, attention deficit/ADHD, and treatment-resistant depression. Amphetamines (with common street names such as uppers or speed) once were available over the counter. The three most common stimulant drugs amphetamine, dextro- amphetamine, and methamphetamine are similar in their effects. In years past, many segments of the population, especially workers with extensive or irregular work hours, took amphetamines orally, often in excessive amounts. As with all stimulants, amphetamines can produce dependence and therefore as their use became commonplace they became iden- tified as having a high abuse potential. A prescribed dose of CHAPTER FOUR STIMULANTS AND ALERTNESS-ENHANCING COMPOUNDS

amphetamines for medical treatments has often been between 2.5 and 15 mg per day. Repeated drug users on a “speed binge” have been known to inject hundreds of times those amounts every 2 to 3 h (Davis 1996). OTC availability of such amphet- amines was stopped in the United States in 1971 by the Controlled Substances Act when they became Schedule II drugs, and they are now legally obtainable only by prescription (Hart and Wallace 1975). However, illegal clandestine labo- ratories produce large amounts of amphetamines, particularly methamphetamines, for illegal distribution. The abuse potential of amphetamines has also led to a reduction in prescription issuance by physicians. Military forces of several countries have expended con- siderable research effort in medical research labs examining the potential for the use of amphetamines in operational applications. For the sake of completeness in this synthesis a limited amount of the performance research done with several of the more prominent stimulants and amphetamines is briefly described in Appendixes A and B. Appendix B also lists details of the U.S. military’s drug management protocol adhered to in the use of stimulants in operations and training. Amphetamine assessment. The use of many stimulants such as amphetamines (with the exception of caffeine, nico- tine, and perhaps modafinil/armodafinil) in any operational environment is inherently risky. [See for example the treatise on methamphetamine and driving behavior risks by Logan (1996, 2002).] Whereas use of amphetamines is not likely to become acceptable operational practice for ameliorating the effects of sleep loss or drowsy driving in drivers of commercial vehicles, urine drug testing and post-crash forensic analyses indicate that some commercial drivers do partake of amphet- amines and other stimulants not usually recommended with intentions of driving. Modafinil Modafinil (ProVigil®), chemical name 2-diphenylmethyl- sulfinyl-acetamide, is a chemically unique, stimulant-like compound that was developed in France in the 1970s–80s (Nishino and Mignot 2005). Modafinil is a primary metabo- lite of adrafinil (Olmifon), a mild CNS-stimulant drug used in Europe to relieve excessive sleepiness and as a vigilance- promoting compound. Adrafinil is a prodrug, primarily metab- olized in vivo to modafinil, resulting in nearly identical phar- macological effects; however, it has not been approved for use in the United States. In 2004, modafinil (as Provigil®) was approved by the FDA for treatment of narcolepsy, for SWSD, and for persistent and excessive daytime sleepiness associ- ated with effectively treated obstructive sleep apnea. In some countries, modafinil is approved for idiopathic hypersomnia (all forms of excessive daytime sleepiness where causes cannot be established). In June 2007, the FDA also approved of a related compound: armodafinil (Nuvigil) as a stimulant- like drug for the treatment of narcolepsy and SWSD, and as an adjunctive treatment for obstructive sleep apnea. Impor- 28 tantly for our purposes here modafinil, adrafinil, and possibly armodafinil would appear to have some application for com- mercial drivers in maintaining alertness, even while driving. In the United States, modafinil is classified as a stimulant, and as a nonnarcotic Schedule IV controlled substance. The use of modafinil therefore requires a prescription. Modafinil is available under the trade names ProVigil®, Vigil®, Alertec®, Modiodal®, and Modasomil®. As with other stimulants, modafinil increases the release of monoamines, but also elevates hypothalamic histamine levels, leading some researchers to consider modafinil a “wakefulness promoting agent” rather than a classic amphetamine-like stimulant. Lagarde and Batejat (1995) described modafinil as a “eugregoric,” meaning “good arousal” (Lagarde et al. 1995). This unique class of eugregoric compounds contains only modafinil, its chemical precursor adrafinil (Milgram et al. 1999), and armodafinil, all three of which were developed as “wake promoting agents” to improve wakefulness. They are sometimes referred to as somnolytics (Mitler and O’Malley 2005). As the primary metabolite of adrafinil, modafinil’s activity is similar; however, adrafinil requires a higher dose to achieve equipotent effects. The basis of modafinil’s uniqueness lies in its ability to stimulate only when stimulation is required; as a result, the “highs and lows” associated with other stimulants such as amphetamines are absent with eugregorics. The lows are sometimes referred to as “recovery sleep” and modafinil, unlike amphetamines, is said not to produce the need for this prolonged recovery, or “rebound hypersomnia.” A totally unique feature of modafinil and adrafinil therefore is that a person wishing to remain awake can use either of them to do so with a far greater level of alertness, but at the same time the compounds will not prevent the person from sleeping if he or she wants to (Buguet et al. 1995; Grady et al. 2010). Modafinil is thought to have less potential for abuse than other stimulants owing to the absence of any significant euphoric or pleasurable effects; therefore, it is thought to be nonaddictive. The central stimulating effect of modafinil shows dose and time-related features (McClellan and Spencer 1998; Nishino and Mignot 2005). Prescription single-dose levels of modafinil are normally between 100 and 400 mg taken orally. Based on their studies, Buguet et al. (2003) recommended 200 mg of modafinil for use in sustained operations. As with some other studies, they demonstrated that the 400-mg dose has not been shown to be more effective than a 200-mg dose. Modafinil achieves maximum levels in the blood between 2 to 4 h after administration, and its half-life ranges from approximately 10 to 15 h (Robertson and Hillreigel 2003). Modafinil exhibits maximum vigilance-enhancing properties, peaking 4 h after a dose of 200 mg. A participant can re-dose with 100 to 200 mg every 4 to 6 h. Occasional side effects such as headache can occur with 300 mg/day doses; and at higher doses (>800 mg) increased blood pressure and increased supine pulse, increased urination, palpitation, tachycardia, excitation, and aggressive tendencies may occur. There also

29 have been some reports of modafinil-inducing skin rashes; a small number of them severe enough to require hospitalization. Since the mid-1980s, numerous clinical trials and studies confirmed the ability of modafinil and adrafinil to increase awakeness and alertness without the serious side effects of dependency. Studies during sleep deprivation found modafinil to be as effective as amphetamines and large doses of caffeine for maintaining vigilance, alertness, and cognitive performance with only minor side effects (Lagarde and Batejat 1995; Lagarde et al. 1995; Pigeau et al. 1995; Akerstedt and Ficca 1997; Baranski and Pigeau 1997; Baranski et al. 1998, 2004; Batejat and Lagarde 1999; Wesensten et al. 2002, 2004; Caldwell et al. 2004; Caldwell and Caldwell 2005). Walsh et al. (2004) demonstrated that the physiologic sleepiness and neurobehavioral deficits that occur during a typical night shift can be attenuated by modafinil. For them, 200 mg of modafinil also had beneficial effects on some measures of executive function (e.g., optimal telegram test involving verbal creative thinking, card sorting, and number sequencing). Mitler and O’Malley (2005) described the research of the U.S. Modafinil in Shift Work Sleep Disorder Study Group, with its concern for shift workers who, like many commercial drivers, suffer at least transiently from effects of both sleep deprivation and circadian misalignment. A Harvard Medical School project enacted a double-blind, placebo-controlled, 3-month study of more than 200 night-shift workers (Czeisler et al. 2005). At baseline, the shift workers were pathologically sleepy, as their Multiple Sleep Latency Test (MSLT) fall asleep times were approximately 2 minutes, they demonstrated significant cognitive impairment (slower reaction times mea- sured by a psychomotor vigilance task), and they exhibited numerous mistakes, near-misses, or accidents at work or while driving home after work. When workers took 200 mg of modafinil at the beginning of their night shift, all of these mea- sures improved substantially. Furthermore, this treatment did not interfere with their ability to sleep during time off duty (Czeisler et al. 2005). On the basis of this and other evidence, the FDA, in 2004, approved modafinil for treatment of excessive sleepiness resulting from SWSD. Together with a program of non- pharmacologic measures to protect sleep time and sleep ability in this shiftwork population, this represents a potentially life- saving treatment for these adults (Mitler and O’Malley 2005). Subsequently, in June 2005, armodafinil (Nuvigil) was also approved by the FDA for treatment of SWSD. This research with modafinil and the subsequent FDA approval of its use for SWSD present distinct implications for practical applications as a fatigue countermeasure for commercial drivers whose shift-work schedules often are “nonstandard.” Additional research is needed to determine appropriate protocols for the use of modafinil and/or armodafinil as potential alertness and fatigue management countermeasures for commercial drivers. The first important study employing modafinil as a stimulant in humans was done by French military medical researchers (Lagarde and Batejat 1995; Lagarde et al. 1995; Batejat and Lagarde 1999), who found that 200-mg doses of modafinil every 8 h reduced episodes of microsleep and maintained more normal (i.e., rested) mental states and performance levels (measured through questionnaires, visual scales, and sleep latency tests) than placebo for 44 h of continuous wakefulness (but not for a full 60 h of sleep deprivation). The modafinil participants sustained a satisfactory level of vigilance with an absence of sleep episodes, unlike the placebo group that gradually declined and slipped into microsleep episodes as one might expect when remaining awake for longer than 24 h. Since that time, military forces in France, the United Kingdom, and the United States have shown a particular interest in modafinil as an alternative for amphetamine— the drug traditionally employed in combat situations where troops face sleep deprivation during lengthy missions. Their respective medical research labs have done experiments on potential operational applications for modafinil. These studies showed that modafinil reduces degradation of cognitive perfor- mance, enhances vigilance, and promotes alertness and arousal during extended or sustained operations. It was claimed that modafinil “could keep an army on its feet and fighting for three days and nights with no major side-effects” (TTCP 2001). Caldwell and colleagues (2000) found that 200 mg of modafinil every 4 h maintained simulator flight performance of military helicopter pilots at or near well-rested levels despite 40 h of continuous wakefulness; however, there were some complaints of nausea and vertigo (attributed to the high dose of modafinil used). In a subsequent flight simulator study with U.S. Air Force F-117 fighter jet pilots, three 100-mg doses of modafinil, administered every 5 h, sustained flight performance within 27% of baseline levels during the later part of a 37-h period of continuous wakefulness. Similar beneficial effects were seen on measures of alertness and cognitive performance (Caldwell et al. 2004, 2009). Further- more, the lower dose of modafinil (100 mg) produced these positive effects without causing the side effects noted in the earlier study (Caldwell et al. 2000, 2009). Caldwell and Caldwell (2005) and Caldwell et al. (2009) suggested that because these and similar studies found such positive results with modafinil, the eugregoric compound is gaining popularity in military communities as a way to enhance the alertness of sleepy personnel. Modafinil is considered safer and less addictive than the amphetamines; it produces less cardiovascular stimulation, has lower potential to exacerbate hypertension and cardiac arrhythmias than amphetamine; and, despite its half-life of approximately 12 to 15 h, the drug’s impact on sleep architecture is minimal. Alternatively, other experimental data suggest that modafinil is less effective than amphetamine (Mitler and Aldrich 2000). At the Walter Reed Army Institute of Research, Wesensten et al. (2002) tested modafinil in 50 healthy adults to determine whether it should replace caffeine for restoring performance

and alertness during 48 h of total sleep deprivation. They reported that performance and alertness were significantly improved by modafinil at 200 and 400 mg relative to placebo, and effects were comparable to those obtained with 600 mg of caffeine. There was a trend toward better performance at higher modafinil doses, suggesting a dose-dependent effect, but the differences between modafinil doses were not significant. Performance-enhancing effects were especially salient during the time frame of 6 a.m. through 10 a.m. They concluded that, as with caffeine, modafinil maintained performance and alertness during the early morning hours, when the combined effects of sleep loss and the circadian performance and alert- ness trough is usually manifest. Few instances of adverse subjective side effects (nausea, heart pounding, etc.) were reported (Wesensten et al. 2002). Thus, equivalent performance- and alertness-enhancing effects were obtained with two drugs (caffeine and modafinil) possessing different mechanisms of action. Wesensten et al. (2002) also concluded that modafinil did not offer significant advantages over caffeine (which is more readily available and less expensive) for improving performance and alertness during sleep loss. A later study at Walter Reed indicated that a single 400-mg dose of modafinil was as effective as 600 mg of caffeine or 20 mg of d-amphetamine for sustaining the simple psycho- motor and cognitive performance of sleep-deprived volunteers for 12 h post-dose (Wesensten et al. 2004a, b). In terms of efficacy alone, these Walter Reed laboratory data suggest that modafinil effects are similar to those of high-dose caffeine and moderate amounts of dextroamphetamine. In a U.S. Air Force 88-h sleep loss study of simulated military ground operations, 400-mg doses of modafinil per day were mildly helpful at maintaining the alertness and performance of sub- jects compared with placebo; but the researchers concluded that this dose was not high enough to compensate for most of the effects of complete sleep loss (Whitmore et al. 2006). A 3-year-long study involving chronic treatment with modafinil was conducted in Europe, where modafinil has been available with a prescription for more than two decades. That study determined that modafinil reduced drowsiness in 83% of hypersomniac patients and 71% of narcoleptics, and the pro- longed use of modafinil for up to 3 years did not exhibit any systematic indication of related health risks (Baranski et al. 2001). Studies of modafinil that were carried on for longer than a month’s duration indicated that modafinil may be effective in appetite suppression and therefore may offer some assistance in weight loss protocols. This topic also requires substantive research to delineate the factors associated with this variable. Because of the importance of sleep disorders in the commercial driving community, it is worth mentioning that modafinil and armodafinil have been used to promote wake- fulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome 30 (as an adjunct for treatment of the underlying obstruction), and SWSD. Bittencourt et al. (2008) reported on a placebo- controlled study employing modafinil with confirmed obstruc- tive sleep apnea patients who also were on effective contin- uous positive airway pressure (CPAP) treatment. The study found that modafinil, used adjunctively with CPAP, reduced daytime subjective sleepiness in obstructive sleep apnea patients who regularly use CPAP. Although participants still experienced some sleepiness, modafinil helped improve objec- tive measures of behavioral alertness and reduce functional impairments. Assessment of modafinil. As laboratory research cited in this review indicates, modafinil offers many of the same stimulant benefits as caffeine and amphetamines, but with slightly different physiological side effects, some which are less offensive, such as not being as threatening to blood pressure as caffeine tends to be. Several of the studies demonstrated the utility of modafinil during circadian lulls of mid-afternoon and after midnight. Importantly, unlike any other stimulant (including caffeine), a person taking modafinil can still decide to go to sleep; that is, to “overrule the stimulating effects” and be able to take a nap without interference from the “drug” (Ballas et al. 2002). That feature can offer a real boost for commercial driving applications, and that aspect of modafinil could be explored in subsequent research programs looking for just such an application. Studies as those described earlier have prompted a call for more research to determine the level of effectiveness of using modafinil in potential operational protocols with commercial vehicle drivers. Of the “newer chemical stimulants” being identified, modafinil (and chemically related compounds) may offer the most significant potential as an efficacious and safe chemical countermeasure to fatigue and could be of assistance to commercial drivers (even for chronic use) in the quest for alertness management in highway driving. In particular, additional research should help to develop a suitable “usage protocol,” including identification of recom- mended dose levels, the time of day of administration, the time of administration within a work shift or during adjustments to shift changes, any limitations for the duration of treatment with modafinil (e.g., weeks or months), and determination of whether or not there are interactions with other chemical compounds that drivers frequently ingest, especially caffeine and antihistamines. Caffeine Caffeine (1,3,7-trimethylxanthine) and the related methylxan- thines theobromine (3,7-dimethylxanthine) and theophylline (1,3-dimethylxanthine) are alkaloid compounds widely found in plants throughout the world. According to the Institute of Medicine (IOM) Committee on Military Nutrition Research (IOM-CMNR 2001), more than 60 different plant species contain caffeine. The primary sources of these compounds are coffee (Caffea arabica), kola nuts (Cola acuminate), tea

31 (Thea sinensis), and chocolate (Coca bean). In addition to appearing in omnipresent coffees, teas, chocolates, and other widely known sources caffeine is also available in alternative, convenient pharmaceutical packages of tablets or pills, from 50- to 300-mg doses (e.g., Vivarin® and NoDoz®), in the form of caffeinated chewing gum (e.g., StayAlert™ or Jolt Energy Gum™), is contained in some candies and breath mints (e.g., HyperMints™ or Euromints™), and is even available as caffeine-charged, bottled, noncarbonated natural spring clear water (e.g., Edge2-0™) and other caffeine-charged water prod- ucts (e.g., Java Water, Aqua Java, Water Joe™, Potenza™, and FYXX Hybrid Water™). Some truck stops sell chocolate- covered roasted coffee beans to munch on to provide drivers with a “special picker-upper” while driving. Also readily available in many grocery stores and in most highway rest stop convenience stores are numerous beverages advertised as “energy drinks,” commonly referred to as functional energy drinks (FEDs), wherein the major ingredient is caffeine, which is usually mixed with other caffeine-like chemicals (e.g., guarana) as well as other psychoactive ingredients. FEDs are described separately in chapter five under supplements. Caffeine is the most widely consumed psychoactive or CNS stimulant in the world (Smith and Tola 1998). In addition to its natural occurrence in some foods and coffee, caffeine is used commercially as a food additive, and as a drug or a component of many pharmaceutical preparations. When administered in the amounts commonly found in foods, beverages, and drugs, caffeine has measurable effects on certain types of human performance. Caffeine use has been associated with increased alertness and enhanced physical performance, and as a countermeasure to the effects of sleep deprivation. Extensive research has been done on each of these effects of caffeine. Interested readers are encouraged to consult IOM’s excellent summary of research findings on the efficacy of caffeine use (IOM-CMNR 2001), and the book Caffeine by Spiller (1998). Caffeine is most often ingested by drinking some of the most popular and ubiquitous beverages such as coffee, tea, coca, colas, sodas, or other soft drinks that contain sizeable amounts of the stimulant. There is a wide range in the amount of caffeine in these beverages. The amount of caffeine in a cup of coffee is dependent on: (1) the source, quality, and quantity of coffee beans used to make the coffee; (2) the distributor’s chemical processing techniques; (3) whether the coffee is in whole-bean form or as coffee grounds; and (4) the particular brewing techniques selected for its prepa- ration. In the United States, brewed cups of regular coffee normally contain approximately 75 to 250 mg of caffeine per 8-ounce cup. Popular specialized coffees served in restaurants; for example, espresso, lattes, and iced coffees vary in portion size (e.g., 8, 12, or 16 ounces per cup) and therefore vary in the amount of caffeine they contain, but rarely exceed 250 to 300 mg per cup. However, some espressos contain more caf- feine, ranging from 10 to 90 mg of caffeine per 1-ounce serv- ing, and therefore have a greater “kick” per cup. Boutique shop 16-ounce coffees may contain as much as 550 mg of caffeine. Decaffeinated coffees generally have less than 10 to 20 mg of caffeine per 8-ounce cup. Ice teas sold commercially have a range of from about 6 mg to 60 mg of caffeine in a typical 8-ounce serving. The FDA limits soft drinks to 71 mg of caffeine per 12 ounces. Depending on the particular brand, many commercial soft drinks (bottle or can) in the United States contain anywhere from 45 to 125 mg of caffeine per 12-ounce drink. Most but not all diet soft drinks are devoid of caffeine. For a compre- hensive chart of the caffeine content of popular ingestibles, including soft drinks, caffeinated waters, chocolates, and medications, see Mitler and O’Malley (2005) and a popular Internet website listing amounts of caffeine in many beverages: http://www.energyfiend.com/the-caffeine-database. Caffeine ingested in beverages (e.g., in coffee) enters the body through the digestive process, and is absorbed by the stomach within 30 to 60 min after oral administration. Caffeine is rapidly and completely absorbed in humans, with 99% being absorbed within 45 min of ingestion. The peak absorption time for caffeine received in pill or liquid form occurs before 60 to 90 min. Plasma concentrations may be influenced by the route and form of administration or other components of the diet, and the peak may range between 20 and 120 min after oral ingestion. Once absorbed, caffeine is distributed rapidly throughout body water. Caffeine is suf- ficiently lipophilic to pass through all biological membranes and it readily crosses the blood–brain barrier. The mean half- life of caffeine in plasma of healthy individuals is normally about 3 to 5 h, although its half-life may range between 1.5 and 9.5 h. This wide variation in reported half-life may be the result of individual variation in excretion rates or whether the individual smokes (which decreases half-life) or uses oral contraceptives (increases half-life). The pharmacological effects of caffeine (similar to those of other methylxanthines) include mild stimulation and wakefulness, the ability to sustain intellectual activity, and decreased reaction times (IOM-CMNR 2001). U.S. Army medical researchers demonstrated that caffeine in chewing gum form (StayAlert™), which promotes caf- feine absorption through saliva in the mouth, exhibits notice- able alerting effects in approximately 7 min. Peak absorption of caffeine from chewing gum occurs in 30 min (Kamimori et al. 2002; McLellan et al. 2003, 2005a, b). This application pro- vides a much faster “picker-upper” when a person is partic- ularly drowsy, but for practical reasons cannot cease work for a nap. Caffeinated chewing gum would appear to offer good application potential for commercial drivers. The observable, subjective effects of caffeine last about 4 h and may include a sense or feeling of experiencing a slightly higher heart rate and elevated body temperature, a noticeable perky mood, increased alertness, and signs of improved cognition (i.e., reaction time and memory) and

physical performance. Caffeine consumed both at rest and during exercise increases a variety of physiological processes (heart rate, respiratory rate, blood pressure), most likely through the secretion of epinephrine, and includes cardio- vascular, respiratory, renal, and smooth muscle effects. Caffeine has been touted as an ergogenic aid for enhancing physical performance, both aerobic and anaerobic functions, and muscular endurance as it increases arousal in the CNS, which may lead to reduced perception of the intensity of physical effort put forth (Cole et al. 1996; Baranski et al. 2001, TTCP 2001; IOM-CMNR 2001). Caffeine use is asso- ciated with a reproducible increase in endurance time in phys- ical activities of moderate intensity and long duration. It has been shown to improve pulmonary function and aerobic per- formance, and it may also improve anaerobic performance while improving orthostatic tolerance as well. In describ- ing caffeine’s effects on voluntary muscle activation, the Hoffman reflex, motor-evoked potentials, self-sustained firing, pain, and sensation, Kalmar and Cafarelli (2004) suggested that caffeine may be useful in the study of central fatigue. Caffeine’s effectiveness in enhancing either physical or cog- nitive performance dissipates within 24 h. The effects of caffeine on cognitive performance are diverse. Behavioral measures indicate a general improvement in the efficiency of information processing after caffeine, whereas EEG data support the general belief that caffeine acts as a stimulant. Studies using event-related potential mea- sures have indicated that caffeine has an effect on attention, independent of specific stimulus characteristics. Behavioral effects on response-related processes are mainly related to more peripheral motor processes. Caffeine has been demonstrated to improve or enhance vigilance and alertness in both rested and sleep-deprived indi- viduals. Caffeine is shown to improve and maintain psycho- motor performance and a variety of cognitive functions during prolonged wakefulness (Hogervorst et al. 1999; Hindmarch 2000). Foskett et al. (2008) demonstrated that prior caffeine ingestion improved soccer players’ passing accuracy and ball control. Military medical research labs demonstrated caffeine to be effective during situations involving combat-like stress (IOM-CMNR 2001; TTCP 2001). Its’ effectiveness is related to the dose of caffeine ingested (Baranski et al. 2001). Owing to its low abuse potential and wide availability, caffeine offers significant utility for use in workplace fatigue countermeasures. For example, caffeine was used successfully to sustain aircrew alertness during flights over Iraq in support of Operation Southern Watch in August 1992 (Belland and Bissell 1994). The IOM report on caffeine states that although both com- mon experience and the results of scientific investigations support the belief that caffeine enhances performance on a variety of cognitive tasks, a review of the experimental literature reveals inconsistencies in the amount of caffeine required to produce positive effects on cognitive behavior. The discrepant findings are explained by differences among experiments in the number of variables, including whether or 32 not subjects were tested following a period in which they had abstained from using caffeine just before the test, the tasks used to assess cognitive behavior, the age and gender of the participants, the subjects’ longer term history of caffeine use, and whether the test subjects were rested or sleep-deprived. There has been some debate about whether caffeine enhances cognitive performance or simply restores degraded perfor- mance following caffeine withdrawal in rested individuals [James 1994, 1995, 1998; for further details consult the full IOM report (IOM-CMNR 2001)]. As is the case with most stimulants, the body adapts or adjusts somewhat to the intake of caffeine, and therefore some tolerance occurs with prolonged use of caffeine. Daily heavy coffee drinkers build up a degree of tolerance to the point that when they want to obtain an acute “jolt” from taking in caffeine, perhaps to temporarily restore alertness, that person needs to take in a higher dose of caffeine to feel the desired effects. This is why commercial drivers attending the FMCSA- ATRI lectures on “mastering alertness and managing driver fatigue” are told as a part of a strategy for fatigue management to use caffeine sparingly most of the time, and to conserve their timing for caffeine intake until they absolutely need a boost (e.g., in the middle of the circadian lull of the mid-afternoon). At that time it is recommended that drivers take in 1 to 2 cups of caffeinated coffee or beverages (O’Neill et al. 1996; Krueger and Brewster 2002, 2005). Chronic high caffeine users, when they abruptly stop, may experience symptoms of withdrawal, including fatigue, depression, headache, nausea, and muscle spasms; the most likely withdrawal symptom is a “caffeine withdrawal head- ache” (Baranski et al. 2001; TTCP 2001). The best way to reduce withdrawal symptoms is to, over time, gradually lower the caffeine dosage (i.e., drink less caffeinated coffee). Drink- ing just another cup of caffeinated coffee usually helps dissi- pate a caffeine withdrawal headache. Some research with caffeine suggests that it can enhance performance on some types of cognitive tasks and elevate some aspects of mood in rested individuals independent of its ability to reverse symptoms of withdrawal and regardless of the background consumption of caffeine. Warburton (1995) demonstrated that caffeine administered in doses of 0.75 mg and 150 mg to adult male, nonsmoking, regular caffeine users, without abstinence from caffeine before treatment, improved attention, problem solving, and delayed recall, and it signifi- cantly improved mood ratings. Rogers et al. (1995), using caffeine doses of 0 (placebo), 70, and 250 mg/day in caffeine users (>200 mg/day) and nonusers (<15 mg/day), demonstrated that although caffeine withdrawal had a negative effect on mood, it did not affect psychomotor performance. Jarvis (1993) reported the results of a large survey on coffee and tea consumption showing a highly significant dose-response relationship between habitual caffeine intake and psychomotor performance, simple reaction time, choice reaction time, inci- dental verbal memory, and visuospatial reasoning. This report demonstrated that tolerance to the performance-enhancing

33 effects of caffeine, if it occurs at all, is incomplete, with the result that higher daily caffeine consumers tend to perform better than do low consumers. By employing a variety of standardized tests, caffeine’s effects on cognitive function and mood can be detected in rested individuals, both users and nonusers of caffeine. Studies demonstrate that 200 mg (or more) of caffeine is efficacious in maintaining or returning cognitive performance to a rested level (Lieberman et al. 1987; Lieberman 2001). Only certain behavioral functions appear to be susceptible to the influence of moderate doses (32–256 mg) of caffeine. In particular, in well-rested individuals, low and moderate doses of caffeine preferentially affect functions related to vigilance (i.e., the ability to maintain alertness and appropriate responsiveness to the external environment for sustained periods of time), but have limited effects on memory and problem-solving abilities. Higher doses of caffeine (above 300 mg) can interfere with the performance of tasks requiring fine motor control (Durlach 1998; Rogers and Dernoncourt 1998) and may even produce other adverse effects, especially promoting high blood pressure (Kamimori 2000; Baranski et al. 2001). With regard to commercial drivers’ use of caffeine, a principal interest is its ability to assist in restoring alertness, especially when a person is at least partially sleep-deprived. Judicious use of caffeine can restore alertness, performance on mental tasks, and positive mood states. Smith and Rubin (1999) found that caffeine had a similar profile to amphet- amines in that caffeine reversed sleep-deprivation-induced longer response times, and reduced the number of errors on a visual vigilance task, as well as the sleep deprivation-induced decrements in a running memory test. Bonnet and Arand (1994) found that caffeine increased alertness and perfor- mance on a visual vigilance task, mental arithmetic tests, and logical reasoning in sleep-deprived subjects. Caffeine has also been demonstrated to be effective in simulated combat- like conditions. The military found caffeine to be an effective cognitive aid in rested, sleep-deprived, and stressed war- fighters (TTCP 2001). Research suggests that doses of caffeine between 150 and 600 mg are effective in alleviating sleep- deprivation-induced decrements in cognitive performance (Penetar et al. 1994; Kelly et al. 1996). Caffeine is also effective in delaying sleep onset in sleep-deprived subjects (Penetar et al. 1993, 1994; Smith 1999; Bonnet 1999). In an attempt to determine if low-dose repeated adminis- tration of caffeine would be effective in work periods requiring extended wakefulness, Wyatt et al. (2004) determined that 0.3 mg of caffeine per kilogram of body weight, administered each hour for 29 h of wake episodes, is effective in countering the detrimental performance effects of sustained operations. In the war zones of Iraq and Afghanistan, U.S. military forces have routinely been issuing caffeinated chewing gum (100 mg of caffeine per stick of gum) for just such countermeasure appli- cations to partial sleep loss (Kamimori et al. 2002; McLellan et al. 2003–2004, 2005). Such a strategy could be evaluated for its application to commercial driving scenarios. Researchers at the Walter Reed Army Institute of Research compared and evaluated several stimulant compounds (including caffeine, modafinil, and dextroamphetamine) for their effects on complex cognitive processes subsumed under the construct of executive functions (Wesensten et al. 2005b; Killgore et al. 2009). Executive functions include a broad spectrum of complex higher-order cognitive abilities necessary to plan and coordinate actions, to monitor and adjust behavior, and to focus attention and suppress distractions. In a double- blind placebo-controlled study, Killgore et al. (2009) directly compared the effects of three stimulants (caffeine, modafinil, and dextroamphetamine) by examining specific aspects of executive function and working memory measured by the Tower of London (i.e., planning and visuospatial working memory), Tower of Hanoi (planning, strategy, sequencing, inhibition of pre-potent responses), and the Wisconsin Card Sorting Test (abstract concept formation, mental set shifting) in individuals deprived of sleep for two consecutive nights. After being awake for 45 to 50 h, participants were tested on computerized versions of the three tests. At the doses tested (caffeine 600 mg, modafinil 400 mg, or dextroamphetamine 20 mg) the modafinil and dextroamphetamine groups com- pleted the Tower of London task in significantly fewer moves than the placebo group, and the modafinil group demonstrated greater deliberation before making moves. In contrast, subjects receiving caffeine completed the Tower of Hanoi task in fewer moves than all three of the other groups, although speed of completion was not influenced by the stimulants. Finally, the modafinil group outperformed all other groups on indices of perseverative responding and perseverative errors from the Wisconsin Card Sorting Test. Killgore et al. (2009) concluded that each stimulant may produce differential advantages depending on the cognitive demands of the task. Caffeine and Driving Performance Although many studies examined either the effects of fatigue on driving or of caffeine on cognitive or psychomotor per- formance, little attention has been paid to the interaction of caffeine and fatigue on driving-related skills (Gibson et al. 2006). Studies reporting the effects of caffeine on actual driving performance usually involved automobile simulators (e.g., Heatherly et al. 2004). Several studies focused on com- parisons of caffeine to nap taking or other sleep-related variables. For example, Biggs and colleagues (2007) studied driver’s perceptions of simulated driving performance after sleep restriction and caffeine. Whereas caffeine improved measures of lane drift, the relationship between perceived and actual performance after fatigue countermeasures remained inconclusive. In a French study, two dozen drivers took an on-the-road driving test between 2:00 a.m. and 3:30 a.m. after being given either a placebo (decaffeinated coffee), regular coffee, or were allowed to take a 30-min nap. Highway lane crossings were counted as the measure of interest because lane crossings are involved in many sleep-related crashes. During the 90-min drives, the decaf drinkers recorded a total of 159 lane crossings while drowsy (during the early morning

drives), compared with just 2 lane crossings during daytime pretest data collection drives. Those who took naps did better than the drivers who drank decaf, crossing lines only 84 times. However, the coffee drinkers (with caffeine) did the best in the early morning drives, crossing lines a total of 27 times (Philip et al. 2006; Sagaspe et al. 2007). In quest of suitable countermeasures to drowsy driving, other researchers sought to combine techniques of napping and ingesting caffeine. Such is the case with car simulator research done by Horne and Reyner (1996), whose studies confirm that consuming caffeinated coffee just before taking a short nap (∼20 min) and then resuming driving may be an effective strategy to sustain acceptable driving performance— a strategy that has been advocated for commercial drivers as well, particularly in the afternoon circadian lull (G. Krueger’s fatigue and alertness courses for FMCSA and ATRI, held more than 100 times from 1996 to 2006). Subsequent research by DeValck and Cluydts (2001) and DeValck et al. (2003) determined that both a 300-mg dose of slow-release caffeine and a 30-min nap were successful in counteracting a driver’s sleepiness in a partial sleep deprivation study. The remedial effect of slow-release caffeine lasted longer than that of the nap and was also effective in afternoon sessions. They declared slow-release caffeine to be a valuable counter- measure, and suggested that it is preferable to even a short nap. Laboratory studies of similar issues, but without including a driving component, appear to verify the utility of the combined countermeasure techniques. Schweitzer et al. (2006) evaluated the effects of combining naps with administration of caffeine on performance and alertness in both laboratory and field settings. In the lab study (a parallel groups design), 68 healthy participants were assigned to 1 of 4 experimental conditions: (1) participants in one group were given an evening nap oppor- tunity before the first 2 of 4 consecutive, simulated night shifts plus placebo taken all 4 nights; or (2) caffeine (4 mg/kg) taken nightly; (3) others got the combination of the nap and caffeine condition; and (4) the fourth group received a placebo. The lab- oratory study found that napping, caffeine, and their combi- nation all improved alertness and performance as measured by Maintenance of Wakefulness Tests and by the Psychomotor Vigilance Task (PVT); however, the combination of napping and caffeine was best in improving alertness. In their field study, 53 shiftworkers who worked nights or rotating shifts were permitted an evening nap on the first 2 of 4 consecutive night shifts plus taking caffeine nightly, versus shiftworkers who took a placebo nightly without being allowed to take naps. Napping plus caffeine improved performance as measured by the Psychomotor Vigilance Task (faster reaction times) and decreased subjective sleepiness in individuals working the night shift. Schweitzer et al. (2006) concluded that napping plus caffeine helps improve performance and alertness of night-shift workers. Parliament et al. (2000) provided a comprehensive review of recent developments in the flavor and chemistry of caffeinated 34 beverages, predominately updating research on coffee, tea, and cocoa. Their collection of 40 papers is based on a March 1999 symposium on the topic to specifically address anti- oxidative phenolic compounds found in the beverages, and to examine health benefits, such as the anticancer, anti-aging, and heart disease prevention properties of these beverages. Select papers in this volume also describe health benefits of “green tea” (Chen and Fong 2000; Hara 2000) and present an analysis of coffee phenols and phenolic acids (Cohen 2000). Assessment of caffeine. In summary, caffeine is a relatively safe and effective means of maintaining or restoring cogni- tive performance even under conditions of operational stress (e.g., Baranski et al. 2001; IOM-CMNR 2001; Caldwell et al. 2009). Caffeine restores cognitive function during prolonged wakefulness and it can enhance certain types of cognitive per- formance, most notably vigilance and reaction times in rested individuals regardless of whether or not they are regular caf- feine users. The doses of caffeine most likely to be effective without causing undesirable mood effects are within the range of 100 to 600 mg. The amounts of caffeine cited for regular soft drinks, or for single cups of coffee, may appear somewhat low com- pared with the doses administered in some of the laboratory experiments cited in this synthesis. However, it is often the number of caffeinated drinks consumed by a person in short duration that determines the amount of caffeine consumed and the resultant effect on the CNS, including impact on alertness, cognitive enhancement, degree of blood pressure changes, nervousness experienced, and other known effects. Heavy caffeine consumers, including many commercial drivers (G. P. Krueger, personal communications, 1996–2006), often drink 10 or more cups of caffeinated coffee or 10 or more caffeinated soft drinks (even FEDs) per day. The paucity of actual highway driving studies examining effects of caffeine suggests that more research on this obvious fatigue countermeasure needs to be conducted to delineate numerous unanswered usage protocol variables for commer- cial driver alertness management and fatigue countermeasure programs. Questions should be addressed that identify for commercial drivers when to use caffeine, in what doses, what format (e.g., beverages, tablets, chewing gum, and timed release capsules), how often, and what effects should be anticipated; for example, clarifying how long before preparing to sleep should one refrain from its use, etc. In particular, additional research should be done on the potential for use of slow-time- released caffeine capsules and on caffeinated chewing gum applications. The studies by Horne and Reyner (1996), those of DeValck and Cluydts (2001), and De Valck et al. (2003), and the work of Schweitzer et al. (2006) suggest that additional research on caffeine, particularly slow-release caffeine, in con- junction with judicious nap taking, may lead to valuable fatigue countermeasure applications for long-haul commercial drivers. Cautions of caffeine use. As with any stimulant there are risks in consuming too much caffeine too regularly

35 (IOM-CMNR 2001). Certainly, it is inadvisable to regu- larly drink too much caffeinated coffee and continually subject the body to a slightly elevated blood pressure. Drinking coffee in moderation is always recommended. Some studies, with caffeine doses ranging from 100 to 600 mg per day, found that caffeine use occasionally may result in mild gastrointestinal problems, insomnia, anxiety, restlessness, diuresis leading to dehydration, and increased physiological tremor. With higher doses of caffeine, intakes of 1 g of caffeine (15 mg/kg), mild side effects have been observed progressing from rest- lessness, nervousness, and irritability to more serious effects such as delirium, nausea, emesis, and neuro- muscular tremors. At extreme high doses (e.g., 10 g) caffeine can cause vomiting, convulsions, and even death. The fatal acute oral dose of caffeine in humans is estimated to be between 10 and 14 g (150 and 200 mg/kg) (IOM-CMNR 2001). Nicotine Nicotine is classified as a stimulant. It is also classified as a relaxant, primarily because it increases levels of dopamine in the brain (a hormone/neurotransmitter that causes sensations of pleasure). Nicotine increases heart rate, blood pressure, and respiratory function. It produces pleasure by attaching to the nicotinic acetylcholine receptor on certain nerve cells, which in response release the chemical signal glutamate, telling connected neurons to release dopamine. The more the nerve cells are excited, the more dopamine is released and the more pleasant the feeling (McGehee et al. 2002). Nicotine is readily available in the form of several tobacco sources, including ubiquitous cigarettes, cigars, and chewing tobacco. It is also available in the form of nicotine skin patches (subcutaneous), nicotine chewing gum (polacrilex), and other products predominately advertised for assistance in smoking cessation plans. Research interest in the effects of nicotine and tobacco smoking on human performance has waxed and waned since the early 1900s (Heishman 1998). In the 1990s, owing to renewed attention from the scientific and public health policy communities, a significant amount of research was conducted in programs such as those sponsored by NIDA. Extensive literature reviews by Sherwood (1993) and by Heishman et al. (1994) generally concurred that nicotine enhances a limited range of behavior and has complex effects on human perfor- mance, but that any performance improvements are small in magnitude. The appearance of these review articles prompted numerous additional studies that examined the effects of nicotine and smoking on performance, especially cognitive functioning (Heishman 1998). Much like the considerations involving caffeine studies, interpretation of the performance effects of nicotine depends in part on whether it was tested under conditions of nicotine- deprivation or nondeprivation. That is, effects are dependent on whether a research subject is in a state of tobacco depri- vation (i.e., nicotine withdrawal) or whether he or she is a nonsmoker and therefore a newcomer to tobacco/nicotine use (Heishman et al. 1994; Ernst et al. 2001). In nicotine-dependent individuals, tobacco deprivation (withdrawal) can impair attentional and cognitive abilities within 12 h of smoking cessation (Gross et al. 1993; Lyvers et al. 1994; Bell et al. 1999). Reinitiating nicotine administration or cigarette smok- ing can reverse such performance deficits to pre-deprivation levels (Parrott and Roberts 1991; Bell and Jacobs 1999). Today, the topic of nicotine deprivation and performance is very much prevalent in transportation industries because, for example, some airlines enforce no-smoking policies for their pilots, potentially bringing about flight performance decre- ments in pilots who are smokers (see flight simulator research on this subject by Mumenthaler et al. 1998, 2003, 2010). Whether improved performance associated with relief from withdrawal should be considered cognitive enhancement, or simply labeled restoral to baseline performance levels, has been questioned (Hughes 1991; Heishman et al. 1994). Heishman (1998) pointed out that few studies examined the cognitive effects of a history of smoking, and research reports do not often report pre-deprivation performance levels of test participants. The absence of such data makes it difficult to determine whether nicotine functions to reverse deprivation- induced performance decrements or if it produces true behav- ioral enhancement. Although nicotine appears to have been shown to, at least in part, reverse deprivation-induced deficits in performance, conversely true enhancement of performance has yet to be clearly demonstrated either in nonsmokers or nondeprived smokers (Heishman 1998). True enhancement would be most effectively demonstrated if nicotine or smok- ing were shown to facilitate or improve performance in non- smokers or in nonabstinent smokers (Heishman et al. 1994; Heishman 1998; Ernst et al. 2001). Relatively few placebo-controlled studies have exam- ined the acute effects of nicotine taken in through smoking (Sherwood 1993; Heishman et al. 1994; Heishman 1998; Ernst et al. 2001). The findings of numerous nicotine studies have been inconsistent (Perkins et al. 1990, 1994; Foulds et al. 1996; Ernst et al. 2001). The results in many studies have been discrepant, including improved performance in motor responses (LeHouezec et al. 1994; Bates et al. 1995), sustained attention, and recognition memory, but no effect or impair- ment in selective attention (Foulds et al. 1996), conditioned learning, and recall memory (Ernst et al. 2001). No studies report true enhancement of sensory abilities, or improvements in cognitive abilities such as problem solving and reasoning (Heishman 1998). Foulds et al. (1996) reported that subcuta- neous nicotine (skin patches) improved response time on a logical reasoning test in nicotine-deprived smokers, but had no effect in nonsmokers. Most study reports do not critique whether laboratory measures generalize to performance in the real world. Ernst et al. (2001) examined the influence of past smoking history on cognitive performance by comparing 4 mg of acute

nicotine administration (polacrilex gum) and placebo in 12-h abstinent smokers to that of ex-smokers and nonsmokers. An improvement effect of acute nicotine administration (independent of smoking history) was seen only with respect to reaction time on a 2-letter search task. Working memory performance was related to smoking history (smokers per- formed most poorly and never smokers were best). A logical reasoning task showed no effects of either acute or chronic nicotine exposure. Ernst et al. concluded that nicotine may influence the focusing of attention in smokers as well as non- smokers, and that trait-like differences in some cognitive domains, such as working memory, may be either long-term effects or etiological factors related to smoking. The literature includes several studies of nicotine and simulator driving performance. Other studies reported nico- tine effects on laboratory tests meant to be representative of driving-like tasks. The studies depict a wide variation in designs, and produce conflicting and somewhat inconclusive results. As one example, Sherwood (1995) examined the psychomotor effects of acute administration of single smoked cigarettes with varying amounts of nicotine (<0.1, 0.6, 1.0, or 2.1 mg) on a 1-h computer-based driving simulation (four times in 4 days) comprising continuous tracking and brake reaction time tasks. Brake reaction times were decreased as they improved over all active treatment levels of nicotine; however, tracking accuracy was enhanced after only two cigarettes of middle strength were smoked. Sherwood concluded that ciga- rette smoking may improve driving performance, and that there may be an optimal nicotine dose for the enhancement of cogni- tive and psychomotor functions. However, making conclusive statements about the effects of smoking based on such short- duration studies (employing only 1 h drives) can be misleading. In a flight simulator study, Mumenthaler et al. (1998, 2003) showed that nicotine improved scores on individual flight tasks such as approach to landing, a task that requires sustained attention; they concluded that nicotine may improve late-day flight performance in nonsmoking aviators. Mumenthaler et al. (2010) also demonstrated that nicotine withdrawal effects for smoker-pilots, who are not allowed to smoke in the flight deck, exhibit adverse affects on their simulator flight performance. Perhaps the most pertinent psychological performance study examining nicotine applications for alertness enhance- ment during continuous operations (but also d-amphetamine) is that of Newhouse et al. (1989, 1992). In that Walter Reed study, nicotine was infused intravenously at doses of 0.25, 0.37, and 0.5 mg after 48 h of wakefulness. They found that nicotine had no significant impact on MSLT measures or on psychomotor performance. Additionally, nicotine did not effectively improve cognitive performance (as measured on several tests in the Walter Reed cognitive Performance Assessment Battery); nor did nicotine improve alertness. This prompted Newhouse et al. (1992) to conclude that nico- tine was “not an effective stimulant for maintaining cogni- tive alertness during sustained performance operations.” 36 Therefore, contrary to widespread and common belief, the study by Newhouse et al. demonstrated that nicotine may not be an effective stimulant for maintaining alertness during sustained performance operations. The ambient smoke associated with burning cigarettes in the cab or operator compartment of one’s vehicle is likely to add to driver drowsiness. This is in part because exposure to tobacco smoke adds to carboxyhemoglobin in the blood, and it cuts down on oxygen flow within the bloodstream (Benignus 1991). In addition, cigarette and cigar smoke tend to be irritants to the eyes and nasal passages. Some commercial drivers insist that during lengthy drives they stop to take a walk- around smoke break to help restore alertness. In so doing, the rest break away from driving, especially the act of walking around produces some recuperative alertness value in the form of overall bodily stimulation. Given Heishman’s (1998) assessments of nicotine’s “restoral of alertness” to smoker withdrawal, and the results of research such as that of New- house et al. (1992), it is reasonable to conclude the recuperation in alertness during the drivers’ smoke breaks is not likely attributable to the nicotine consumed per se, as much as it is probably the result of the “restoral effect” for nicotine deprived smokers, and to the physical stimulation effected by the exer- cise gained by walking around in the fresh air outside the truck. Research sponsorship. Turner and Spilich (2006) reviewed a sample of 91 published papers investigat- ing the effects of tobacco or nicotine use on cognitive performance. This review is cited here because Turner and Spilich’s principal aim was to determine if the pat- tern of conclusions drawn by researchers acknowledg- ing tobacco industry financial support differed from the pattern of conclusions drawn by researchers who apparently did not have tobacco industry support. Scientists acknowledging tobacco industry support typically reported that nicotine or smoking improved cognitive performance, whereas researchers not report- ing financial support from the tobacco industry were more nearly split on their conclusions. The authors con- cluded that the existence of a possible bias in the pub- lished literature according to a funding source must be given serious consideration (Turner and Spilich 2006). The same cautions should pertain to pharmaceutical industry-sponsored studies of any chemical substance or new drug. Assessment of nicotine. The health risks of tobacco use and smoking have been well-publicized for more than a quarter of a century and by now should be well-known by everyone. Risks of cancer, heart and lung disease, hypertension, and cardiovascular and circulatory problems prevail as health risks from smoking and tobacco use. For all of these health- risk-related reasons, this synthesis does not support recom- mendations for use of nicotine-containing tobacco (cigarettes, cigars, or chewing tobacco) for maintaining alertness during commercial driving. Nor does it support nicotine administra- tion by means of skin patches or gum form with commercial drivers, although more research on these aspects of the nico- tine topic may be warranted.

37 Nicotine Treatment for Smoking Cessation Nicotine polacrilex gum, when used properly, has been demonstrated to be an effective medication for treatment of nicotine dependence (U.S. Surgeon General’s Report 1988). Nicotine polacrilex can provide therapeutic effects such as the reduction of tobacco withdrawal symptoms, reduction of the tendency to smoke cigarettes, reduction of the effect of relapse factors such as weight gain, and possibly reduction of urges to smoke (Henningfield et al. 1990). However, all of these actions of nicotine are related to the dose level actually being obtained, and inadequate nicotine doses may produce no beneficial effect (Henningfield and Woodson 1989). Often, it appears that patients use nicotine polacrilex with insuffi- cient instruction either to obtain adequate dose levels or to achieve specific benefits (Cummings et al. 1988; Jarvik and Henningfield 1988). For many patients who were unable to quit smoking with the use of nicotine polacrilex, the problem may have been a failure to obtain the medication in suffi- cient doses and not medication failure per se (Henningfield et al. 1990). Insomnia and daytime fatigue and sleepiness are recog- nized as one of the criteria for nicotine withdrawal syndrome (Underner et al. 2006). Nicotine replacement therapy could be potentially hazardous to individuals whose occupations require alertness, such as drivers of commercial vehicles, because of the effect of the nicotine replacement disrupting sleep and causing unusual and distressing dreams (Colrain et al. 2004). When nicotine is placed in the mouth, the amount actu- ally absorbed through the buccal mucosa is determined by the pH of the salvia, because nicotine is a weak organic base that is best absorbed in the nonionic form. Nicotine absorption can be substantially impaired by consumption of acidic drinks such as coffee and carbonated beverages (fruit juices and soft drinks) either while using the polacrilex (chewing gum) or immediately before using polacrilex. For details, see a review, and published research on this topic by Henningfield et al. (1990). Smoking Cessation Drug Warning At a time when many commercial drivers are attempting to stop smoking or to cease using chewing tobacco, it is important to note that use of a popular smoking-cessation prescription drug, varenicline (Chantix™), warranted dangerous side effects warnings, as issued by three U.S. federal agencies, the FDA, FAA, and FMCSA (May 2008). The drug acts at sites in the brain affected by nicotine and may help those who wish to stop smoking by providing some “nicotine-like” effects to ease the withdrawal symptoms and by blocking the effects of nicotine from cigarettes if users resume smoking. An Institute for Safe Medication Practices review of hundreds of “adverse event” reports (2007) forwarded to the FDA by Chantix maker Pfizer Pharmaceutical identified immediate safety concerns about the use of varenicline among persons operating aircraft, trains, buses, and other vehicles or in other settings where a lapse in alertness or motor control could lead to massive, serious injury. The Institute reported that more than 1,000 complications linked to varenicline were reported in the first quarter of 2008, including 15 traffic accidents, 52 incidents of loss of consciousness and black- outs, and 50 deaths. On May 16, 2008, the FDA became convinced that varenicline (Chantix™) had serious side effects and exhibited symptoms including anxiety, nervousness, tension, depressed mood, unusual behaviors, and thinking about or attempting suicide. The FAA removed Chantix™ from the list of medica- tions considered safe for pilots and air traffic controllers. On May 23, 2008, the FMCSA issued an advisory warning stating that varenicline (Chantix™) may adversely affect commercial drivers’ ability to operate vehicles safely, and that medical examiners should not certify a driver taking Chantix™. Another medication used for smoking cessation, bupro- pion (Wellbutrin® or Zyban®) is also associated with adverse effects, including insomnia, tremors, agitation, rash, and confusion. Kolber et al. (2003) and Ross and Williams (2005) reported that with concomitant use of tramadol (Ultram®) the threshold for seizure is lower, and interactions of the two medications promotes additional side effects. Erectile Dysfunction (anti-impotence) Medications Erectile dysfunction (ED) medications do not fit neatly into the category of stimulant drugs; however, for the sake of including them in this synthesis, their description is presented here. Several medications used for treatment of ED are some of the most popular and widely used drugs in the United States and Europe (e.g., sildenafil and vardenafil) (Kloner and Zusman 1999). Contrary to popular belief, silden- afil is not an aphrodiasiac, does not work in the absence of sexual arousal, and does not make a potent man more virile (DeMey 1998). After oral administration, sildenafil is rapidly absorbed, reaching peak plasma concentrations in 30 to 120 min. For pharmacokinetic details on sildenafil see Johnson and Lewis (2006). Vardenafil (Levitra®) was introduced in the United States in 2003, but currently is not one of the most widely pre- scribed treatments for ED, as other newer ED medications are more popular. After oral administration of vardenafil, peak plasma concentrations are obtained within 30 to 60 min. Vardenafil and its active metabolite have a terminal half- life of approximately 4 to 5 h (Johnson et al. 2006). Johnson et al. (2006) pointed out that although they are relatively safe, the several ED medications available have certain side effects that present a possibility of creating safety

hazards in aviation operations. One such potential side effect is a condition known as “blue tinge”—the inability to dis- criminate between blue and green colors, which could hinder execution of certain tasks such as a pilot relying on instru- ments during adverse meteorological conditions and/or dur- ing night flights (Borrillo 1998). Additionally, vardenafil has been shown to potentiate the hypotensive effects of nitrates commonly employed in treatment of certain heart conditions (Bischoff 2004). Work at FAA’s CAMI is directed at chemical postmortem analysis of biological samples taken from pilots who died in airplane crashes. Those numbers demonstrate increases in postmortem ED medications found in pilots. What effect or role the ED medications have played in recent aircraft crashes has not yet been determined (Johnson et al. 2006; Johnson and Lewis 2006). Monitoring those investi- gations is warranted to determine if there are safety-related parallels in the commercial driving industry. No reports evaluating the cognitive performance effects of taking ED or anti-impotence medications were located. However, unconfirmed news accounts report that several military forces have been doing exploratory research on sildenafil (Viagra®) to assess its efficacy in assisting high- altitude fighter pilots to fight off fatigue and “foggy heads.” The hypothesis is that the ED family of drugs might be 38 effective in these conditions because when there is a long shortage of oxygen, such as during flight at high altitude, it leads to pulmonary hypertension (“high blood pressure in the lungs”) and the drugs could help fight that condition by improving the flow of oxygen through the body. This may be counteracted by supplemental oxygen available or required for pilots flying above certain altitudes. Israeli Air Force research began after some exploratory work in other low oxy- gen environments, such as those concerning mountain climbers on extremely high mountain climbs (Times of London, Feb. 7, 2008). The active ingredient in Cialis® (tadalafil) helped climbers ward off fatigue and dizziness at greater altitudes (Richalet et al. 2005). ED medication assessment. Although neither potential benefits nor significant problem areas were identified with the use of ED medications during driving operations, it is incumbent on the commercial driving community to continue to monitor research results and other medical developments, particularly any revealing adverse events attributable to use of these popular medications. Table 3 summarizes in tabular form some of the basic infor- mation concerning stimulants and wake-promoting chemical substances and their possible uses. Category Availability Use/Effect Comments Permitted for CMV drivers Caffeine Ubiquitous, in coffee, tea, soft drinks, energy drinks, tablets, and so on Alertness maintenance, slight boost to energy Need for operations usage protocol and guidance; highlight risks; e.g., high BP Nicotine Tobacco use, smoking, skin patches Soothing with smoking habit Not effective for restoring or maintaining alertness performance; causes cancer Functional Energy Drinks (FEDs) [see see chapter five: nutritional supplements] Energy drinks, chews, candies, supplements Popular drinks with hopes for slight stimulant effects No substantive research data on effects; risk of taking too many FEDS, interactions with other chemicals possible Modafinil Only with prescription; mostly as prescription for ProVigil® for SWSD or ADHD Rx for SWSD, ADHD, Narcolepsy Stimulant without untoward effects Promising for alertness, but not yet commonly accepted for CMV driver use Need more research and usage protocol guidance Generally Not Permissible for CMV Drivers Amphetamines: Legally available by prescription for medical treatment only, 391.41.b-12 Stimulation helps sustain performance, but with other undesirable effects Risk of loss of CDL or job if caught using without prescription d-amphetamine Controlled operational applications limited to military Used for short-duration military applications; use not likely permissible in CMV operations Methamphetamine Methylphenidate Cocaine Illicit; bought on the streets Recreational, addictive Risk of loss of CDL, job Prescription and on Treatment for ADHD Not practical, risk of abuse the street Ephederine FDA cautions; still available Mostly a weight loss fat burner Can be dangerous BP = blood pressure; SWSD = shiftwork sleep disorder; ADHD = Attention Deficit Hyperactivity Disorder. TABLE 3 LIST OF STIMULANTS AND WAKE PROMOTING SUBSTANCES