+ Presenter: Mitchell A. Garber, MD, MPH, MSME, Senior Managing

Presenter: Mitchell A. Garber, MD, MPH, MSME, Senior Managing Consultant, Engineering Systems, Inc. Schedule II Opioids and Stimulants: Opinions of the Medical Expert Panel regarding Commercial Driver Performance and Crash Risk

Roadmap Research The Questions MEP Meeting Medical Expert Panelists Initial Opinions 2 Q1a Q1b Q2 Q3 Additional Opinions

Research Questions 3 Q1a: What is the relationship between licit use of prescribed Schedule II opioids or stimulants and the risk of a motor vehicle crash? Q1b: What is the relationship between licit use of prescribed Schedule II opioids or stimulants and indirect measures of driver performance? Q2: Are the effects of licit use of prescribed opioids or stimulants measureable by serum levels? Do these effects remain consistent or vary based on metabolism or other pharmacokinetic parameters? Q3: Do the effects worsen or improve when: 1) drug-drug interactions take place with other Schedule II or over-the-counter medications; or 2) the drug has been chronically administered over a period of time (stable use)?

The MEP Meeting Medical Expert Panelists, FMCSA personnel, and members of Acclaro convened from 9 AM to 5 PM on July 8, 2014 to discuss Acclaro’s findings The purpose of the meeting was to provide opinions to the Medical Review Board that will aid in the decision-making process 4

Medical Expert Panel Medical Expert Panelists Mitchell A. Garber, MD, MPH, MSME, Senior Managing Consultant, Engineering Systems, Inc. Tara Gomes, MHSc, Assistant Professor, University of Toronto, Canada Gary G. Kay, PhD, President, Cognitive Research Corporation and Associate Professor, Georgetown University School of Medicine, Washington, DC Nicholas Lomangino, MD, Acting Manger, Medical Specialties Division, Office of Aerospace Medicine, FAA Carl A. Soderstrom, MD, Chief Medical Advisory Board, Maryland Motor Vehicle Administration 5

Initial Opinions of the MEP The panel recognizes that driving complexity is increased in Commercial Motor Vehicles (CMVs) compared to non-commercial passenger vehicles and that the outcomes of CMV crashes pose significantly greater potential for adverse outcomes The severity of the underlying condition for which medication is being prescribed should be considered when determining whether an individual is deemed medically fit to operate a CMV The pressures of commerce make it difficult for CMV drivers to self-regulate their driving while using medications. Behavior that reduces potential exposures (e.g., avoiding traffic, driving only during the day, only taking familiar routes, or not driving entirely) is generally not an option that is available to CMV drivers who must drive as a condition of their occupation The panel noted that additional relevant studies would have been identified and included had more general search terms (such as “cogn*” or “psychomotor”) been utilized in the review of the literature. The search terms utilized by the Acclaro team were more specific in nature 6

Research Question 1a What is the relationship between licit use of prescribed Schedule II opioids or stimulants and the risk of a motor vehicle crash? Evidence base n 25 7

Q1a Findings Opioids There is moderate evidence that licit use of opioids increases the risk of a motor vehicle crash Several studies link opioid use to increased risk of driver fatalities, driver injury, crash risk, and unsafe driver actions Most studies show increased risk. However, many of the findings are drawn from the same dataset, and many classify all opioids together. Results for specific opioids are more limited and less convincing 8

Q1a Findings Stimulants There is weak evidence that licit use of stimulants increases the risk of a motor vehicle crash Most evidence pertains to amphetamines and comes from a large European study which showed an increased risk of driver fatalities, driver injury, and crash risk The use of stimulants to address driver medical conditions such as attention deficit hyperactivity disorder (ADHD) may improve driver crash risk based on one small study. Further research is required 9

Q1a: Opinions of the MEP Opioids Use of licit opioids conveys at least a modest increased risk for fatal accident involvement, injury accident involvement, and crash causation These risks appear to rise as prescribed dose increases 10

Q1a: Opinions of the MEP Stimulants Licit use of stimulant medicine for treatment of ADHD likely reduces the increased crash risk associated with ADHD. However, timing of stimulant dosing in ADHD patients can be complex, and risk may remain elevated in treated ADHD patients at times when stimulant activity is absent or waning Amphetamines and similar stimulants have a very high tendency for abuse Use of amphetamines outside of closely monitored treatment of ADHD poses a substantially increased crash risk 11

Research Question 1b What is the relationship between licit use of prescribed Schedule II opioids or stimulants and indirect measures of driver performance? Evidence base n 29 12

Q1b Findings Opioids There is moderate evidence that licit use of opioids negatively impacts indirect measures of driver performance Studies generally found indicators of impairment, especially for drug-naïve1 individuals. Impairment was most pronounced on psychomotor vigilance tasks related to pertinent driving skills such as attention, vision, auditory perception, and reaction time Fewer studies included driving simulators or roadside driving tests; however, studies that used these assessments were not significant. Findings vary across drug and dose Individuals who have no established tolerance or habituation to a drug 1 13

Q1b Findings Stimulants There is weak evidence that licit use of stimulants positively impacts indirect measures of driver performance among drivers with ADHD based on consistent findings among a small number of studies Studies suggest that stimulants improve performance among adults with ADHD on psychomotor vigilance tests related to reaction time and complex tasks, as well as performance in a driving simulator related to speeding and weaving There is moderate evidence that licit use of stimulants has minimal or positive indirect measures of driver performance among drivers taking low doses of stimulants Studies found limited or no negative outcomes and some small improvements in psychomotor vigilance tasks related to reaction time, coherence, car-following, accuracy, and speed. Effects tend to be dose specific, and may only be present for the use of small or moderate doses There are mixed results of the effect of stimulants on sleep 14

Q1b: Opinions of the MEP Opioids Although there is some information from laboratory testing to suggest that opioids may impact driving related abilities, the evidence is insufficient to determine whether use of opiate medication causes impairment on indirect measures of driver performance Most studies have investigated single, acute, low doses of these medications with young, healthy subjects. The tests used in these studies have failed to adequately assess essential driving ability domains Most of the measures are brief in duration and therefore do not address critical abilities such as vigilance or sustained attention Studies that have used high fidelity driving simulators or ‘on-theroad’ driving tests have failed to show impairment in maintenance of lane position following administration of opioids. However, in these studies the driving challenges encountered by the subjects when driving may have been inadequate to detect a change in crash likelihood or other performance deficits 15

Q1b: Opinions of the MEP Stimulants Licit use of stimulant medicine for treatment of ADHD has been repeatedly shown to improve the driving performance of treated subjects. However, the beneficial effects are limited to the time during which the medicine is present at therapeutic levels Caution must be exercised to avoid the medication adversely effecting normal sleep; insomnia is a very common adverse event which could result in a performance deficit in driving due to sleep loss Schedule II stimulants are not appropriate as an occupational counter-fatigue measure 16

Research Question 2 Are the effects of licit use of prescribed opioids or stimulants measureable by serum levels? Do these effects remain consistent or vary based on metabolism or other pharmacokinetic parameters? Evidence base n 14 17

Q2 Findings There is moderate evidence that the effects of opioids and stimulants are measureable by serum levels There are consistent findings across studies that serum levels are comparable to other methods in investigating relationships between licit drug use and driving impairment. However, this relationship likely exists for only certain Schedule II medications, and may also be subject to floor or ceiling effects Investigating relationships by serum level allows for a better understanding of possible variation due to differences in how individuals metabolize medicines 18

Q2: Opinions of the MEP The effects of licit use of opioids and stimulants cannot be determined by serum levels; however, very high serum levels are likely indicative of tolerance or substance use disorders The pharmacodynamics1 do not remain consistent; they vary by metabolism and other pharmacokinetics.2 They also vary considerably across individuals There does not appear to be any data suggesting a minimum threshold level or time-course for impairment. This applies to the entire period of drug exposure from onset, to peak, to withdrawal The relationship between drug concentration and effect 1 The process of drug absorption, distribution, metabolism, and excretion 2 19

Research Question 3 Do the effects worsen or improve when: 1) drug-drug interactions take place with other Schedule II or overthe-counter medications; or 2) the drug has been chronically administered over a period of time (stable use)? 20 Evidence base n 19

Q3 Findings Drug-Drug Interaction The evidence pertaining to whether Schedule II opioids and stimulants interact with other Schedule II or prescription medications is unacceptably weak Limited data investigates the question of interactions, and what data do exist, conflict. Findings are likely drug and dose specific, and an insufficient evidence base exists at this time to adequately address the question 21

Q3 Findings Stable Use There is moderate evidence that stable use of Schedule II opioids is associated with reduced negative impacts Consistent data suggest that the negative impacts of opioids on driving and driving related skills diminish over time when doses remain stable. This is not the case for positive impacts, such as those that may be associated with methadone maintenance treatments. However, negative effects of opioids may still remain, even in chronic users There is weak evidence regarding the impact of chronic use of stimulants on driving or driving related skills. There is limited, thus, inconclusive evidence on this topic. 22

Q3: Opinions of the MEP Drug-Drug Interaction As with any drug, there are likely to be drug-drug interactions. Research studies have not addressed the effects of these interactions with Schedule II drugs due to logistical and other complications While it is certainly true that not all combinations of drugs can be analyzed, a review of dispensing data (e.g., IMS databases) may indicate specific combinations of drugs that are frequently coprescribed and which may merit further investigation 23

Q3: Opinions of the MEP Stable Use Chronic use of opioids in the community does not equate to stable use of the medications Opioids are typically prescribed for use as needed (PRN) and are often titrated to pain level, which may vary substantially over time Population data suggest that chronic use of opioids is likely to lead to dose escalation over time and possibly iatrogenic dependence/addiction There is limited evidence that impairment resulting from stable opioid use diminishes over time. However, the studies that examined this issue failed to establish a safe level of use at the level of the individual 24

Q3: Opinions of the MEP Stable Use Conditions requiring chronic opioid treatment may be incompatible with commercial motor vehicle operations The effects of the licit use of stimulant medication for the treatment of ADHD are unlikely to be significantly changed due to chronic use, although users may experience periodic dose adjustments Following such a dose adjustment, a period of assessment with regard to adverse effects might be required after dose adjustments Other use of stimulants is associated with a potential for substance use disorder 25

Conclusions of the MEP 26

Conclusions of the MEP Opioids It is the opinion of the panel that the licit use of schedule II opioids conveys at least a moderate increased risk for fatal accident involvement, injury accident involvement, and crash causation There is some information from laboratory testing suggesting that opioids may impact driving-related abilities; however, the evidence is insufficient to determine whether the use of opioids causes impairment on indirect measures of driving performance Population data suggest that chronic use of opioids is likely to lead to dose escalation and possibly iatrogenic dependence/addiction over time; the panel believes conditions requiring chronic opioid treatment may be incompatible with the routine successful completion of driving tasks 27

Conclusions of the MEP Stimulants The licit use of stimulant medication for ADHD likely reduces the increased crash risk associated with ADHD, though timing of stimulant dosing can be complex and positive effects are limited to the time during which the medicine is present at therapeutic levels The use of amphetamines, which are highly addictive, outside of closely monitored ADHD treatment poses a substantially increased crash risk. The effects of the licit use of stimulants for ADHD treatment are unlikely to change significantly with chronic use 28

Conclusions of the MEP Opioids and Stimulants For both opioids and stimulants, the panel believes the effects of licit use cannot be determined by serum levels, and effects will vary across individuals based on metabolism and other pharmacokinetic factors As with any drug, there are likely to be drug-drug interactions with both opioids and stimulants; however, research studies have not addressed these effects due to various complications. The panel also believes that throughout the literature, research findings underestimate the actual impact of the use of both opioids and stimulants There are other medications that may significantly impact CMV drivers that are not well studied in the literature to date. They suggest that additional studies would be beneficial to evaluate these substances 29

Additional Opinions of the MEP 30

31 Opportunities for Further Research There are medications that may be having a significant impact on the CMV driver population, given their common utilization in the United States, but which are not well-studied in the literature reviewed to date. The panel recommends that further review of the scientific literature be completed, and in many cases, additional studies be funded, to evaluate the impact of the following medications on CMV driver safety. Other drugs to research: Benzodiazepines Diphenhydramine and other first generation antihistamines Non-schedule II stimulants, including phentermine, modafinil and armodafanil Prescription opiates most commonly utilized in the US, including: oxycodone, hydrocodone, and meperidine, among others

Avenues for Future Research Examine the patterns of actual use of medications and how this impacts CMV driver safety Examine the hypothesis that CMV drivers with ADHD have decreased crash risk with amphetamine use Examine the safety implications for individuals withdrawing from stimulants used for the treatment of ADHD. Are performance deficits evident at the end of the shift? Are performance deficits evident the following day due to secondary insomnia? Examine the effects of shorter acting and longer acting amphetamines, including patterns of use and impact on alertness Examine the use patterns of stimulants. Are drivers using amphetamines for weight loss? Are CMV drivers using phentermine to lose weight? 32