Performance A Review of Findings for the Medical Review Board July 29 2014 Roadmap Purpose Background Overview of Research Questions Search Methodology Q1a Q1b Q2 Q3 Conclusion ID: 693608
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Slide1
Prepared by:
Schedule II Opioids and Stimulants & CMV Crash Risk and Driver
Performance:
A Review of Findings for the Medical
Review Board
July
29,
2014Slide2
RoadmapPurposeBackground
Overview of Research Questions Search Methodology Q1a
Q1b Q2 Q3
Conclusion2Slide3
PurposeFMCSA asked Acclaro Research Solutions, Inc. to
conduct a systematic literature reviewThe review looks at how the licit use of Schedule II opioids and stimulants may impact the risk of CMV crashes or indirect measures of driver performanceThese findings, along with input from an expert review panel and FMCSA’s Medical Review Board, are used to inform policy and decision-making
3Slide4
BackgroundSchedule II Drugs
Controlled Substances Act (CSA) became law in 1970Regulates the manufacture, possession, importation, and distribution of certain substances5 classifications (schedules) of controlled substancesSchedule
II drugs have medical application but also carry a high risk for both psychological and physical dependenceSchedule II includes a variety of stimulants, depressants, and a large number of opioids
This study focuses on Schedule II opioids and stimulants4Slide5
Research QuestionsQ1a: 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)?5Slide6
Search Methodology
Defined search terms a priori"potentially driver-impairing" OR "PDI" OR "drug driving" OR "drugged driving"…Systematically searched for full-length articles published January
1, 2006 to December 2013Retrieved abstracts reviewed for inclusion/exclusion
Articles meeting inclusion standards were retrieved in full text and reviewed thoroughly for final inclusionIncluded articles evaluated for quality of evidenceResearch databases (n=11)Academic Search Premier, Business Source Complete, Cochrane Library, CINAHL, Embase, Health Business Elite, National Guideline Clearinghouse, PubMed, ProQuest, Science Direct, TRID
Commercial, non-profit, and government websites (n=18)National Transportation Safety Board, American Pain Society, FMCSA, FDA, American Trucking Association, etc.Reference sections of all included articlesSearch Strategy
6
Sources SearchedSlide7
Search Methodology
Published in EnglishFull-length articlesn=10 or more subjects enrolled
Most subjects must be 18+ Study on the licit use of prescribed Schedule II opioids or stimulants
If illicit use is included, the effects must be separableIf drugs other than Schedule II opioids or stimulants are included, the effects must be separablePublished after January 1, 2006The most complete publication will be the primary reference
Inclusion Criteria7Slide8
Evaluation of Quality of Evidence and Characterization of Evidence
Included articles were reviewed for bias using the standards of the Cochrane Bias Methods GroupStudies rated in discrete categories such as selection bias, attrition bias, reporting bias, etc.All studies were deemed acceptable quality and none were droppedOverall body of evidence for each research question and topic was rated on a four-point scale:
Strong: Evidence is convincing; highly unlikely new evidence will change conclusionsModerate: Evidence is somewhat convincing, small chance new evidence will change conclusions
Weak: Some evidence exists, but there is a reasonable chance new evidence would overturn conclusionsUnacceptably Weak: Insufficient evidence to draw conclusions8Slide9
Research Question 1aWhat is the relationship between licit use of prescribed Schedule II opioids or stimulants and the risk of a motor vehicle crash?
Evidence base n=259Slide10
Q1a: Opioids & Crash Risk
10
Opioid use & driver
fatality
Opioid use & driver
injury
Opioid use & crash
risk
Opioid use & unsafe driver actions
Original Research Articles
(n=3)
All
found
significantly increased adjusted
OR
[*4,
*6, 12]
*
Two studies used same data set
(
n=5)
Found
significantly elevated and increased adjusted
OR
[*4,
*5, *6]
Increased odds for drivers taking opioids; highest odds were for drivers taking 100-199 MEQ [13]
Increased odds for older
female drivers compared to older males [14]
*
Three studies
used
same data sets from previous cell
(n=3)
Increased risk using crude OR [7]
Increased IRR
[11]
No significant increase in OR [16]
(n=2)
Elevated
risk for
women (aged 25-55)
&
men (aged 25-65)
[
10]
Increased
adjusted OR of at least one unsafe driver action for CMV
drivers [17]
Systematic Reviews
N/A
N/A
(n=7)
No increased risk [20, 25]
Limited evidence [18]
Insufficient data [19]
Mixed results [22]
Increased risk through meta-analysis [21, 23]
N/A
OR= Odds Ratio; IRR= Incident Rate Ratio; SIR= Standard Incidence
Ratio; MEQ= Morphine EquivalentSlide11
Q1a Specific Opioids & Crash Risk
Codeine
Morphine
Natural Opium Alkaloids
Methadone
Original Research Articles
(n= 4
)
Increased SIR; risk decreased and was non-significant
when co-prescriptions were excluded [1]
Increased IRR when starting prescription and four weeks after [11]
No difference in codeine prevalence between roadside controls and injured drivers [8] or fatally injured drivers [12]
(n=1
)
No difference in prevalence between roadside controls and injured drivers [8]
(n=1
)
Increased crash
risk from national registry database [3]
(n=2)
Increased risk of crash [2]
Methadone was more prevalent in roadside drivers than drivers involved in accidents [8]
Systematic Reviews
N/A
N/A
N/A
(n=1)
Increased involvement in accidents & increased responsibility for accidents [24]
OR= Odds Ratio; IRR= Incident Rate Ratio; SIR= Standard Incidence Ratio
11Slide12
Q1a: Stimulants & Crash Risk12
Amphetamines
Methylphenidate
Original Research Articles
(n=5)
Increased
risk of drivers being involved in an accident, being seriously injured, and being
killed [*4,
*5, *6, *7, *8]
*
All studies used the same data set
(n=1)
Stable use improved self-reported
risky
driving
in young
drivers with
ADHD [9]
Systematic Reviews
(n=1)
Included four relevant articles; only one showed
impairment 23]
N/ASlide13
Q1a ConclusionsThere is moderate evidence to support the contention that licit use of opioids increases the risk of a motor vehicle crash.
Several large and recent studies link opioid use to increased risk of driver fatalities, driver injury, crash risk, and unsafe driver actions. Most identified studies show increased risk. However, many of the findings are drawn from the same large European dataset, and many of them also classify all opioids together. Results for specific opioids are more limited and less convincing
.
13Slide14
Q1a ConclusionsThere is weak evidence to support the contention that licit use of stimulants increases the risk of a motor vehicle crash.
Most of the available 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 ADHD may improve driver crash risk based on one small study. Further research is required.
14Slide15
Research Question 1bWhat is the relationship between licit use of prescribed Schedule II opioids or stimulants and indirect measures of driver performance?
Evidence base n=2915Slide16
Q1b: Opioids & Indirect Measures
16
Opioids
Original
Research Articles
Systematic Reviews
(n=2)
Impairment
of driving related skills in chronic opioid users compared to healthy controls [33]; but no impairment was shown in actual driving [32]
(n=6)
Limited evidence [18]
No conclusions; insufficient data [19]
Some
i
mpairment
from stable opioid use found in one-third of studies; strong evidence for no impairment
on
simulator
[20]
Minor cognitive deficits for long-term use; impairment associated with higher doses [47]
Causes some moderate impairment; effects are dependent upon type and dose of opioid [23]
Found two groups of users: new opioid users/recent dose increase (naïve users¹) who are likely to demonstrate impairment; and chronic users who are not impaired by use [25]
¹naive users refers to subjects who are expected to respond differently than chronic drug users due to limited or no prior exposure to the drugSlide17
Q1b: Opioids & Indirect Measures: Original Research
Codeine
Codeine/
Paracetamol
Oxycodone
Oxycodone/
Paracetamol
Morphine
Hydrocodone/
Hydromorphone
&
Meperidine
Methadone
(n=1)
No increased impairment in reaction time for chronic pain patients
[30]
(n=1)
No significant differences between three drug doses and placebo on driving simulator
tasks [26]
(n=4)
No
impairment in psychomotor skills after 10
mg [35,
36, 37]
,
but
one study found
significant impairment after 20
mg [36]
Failed
to show non-inferiority
[28]
(n=1)
Three significant differences were found at low dose (5/325 mg; easy & hard tracking & divided attention task
);
two differences were found at the high dose (10/650 mg; hard tracking test & divided attention
) [38]
(n=1)
High dose morphine group performed significantly worse than low dose morphine group and placebo group; placebo group out-performed both morphine
groups [36]
N/A
(n=3)
No differences on five tests between peak and trough groups; peak group performed better on some tasks [27]
Methadone maintenance (MM) improved cognitive performance after 3 months [29]
Controls out-performed MM and abstinence group; abstinence group out-performed MM [31]
17Slide18
Q1b: Opioids & Indirect Measures:Systematic Reviews
Codeine
Codeine/
Paracetamol
Oxycodone
Oxycodone/
Paracetamol
Morphine
Hydrocodone/
Hydromorphone
&
Meperidine
Methadone
(n=1)
Found suggestive evidence of impairment [48]
N/A
(n=1)
Found suggestive evidence of impairment in attention, divided attention, psychomotor skills
, reaction test,
and visual
functions; a dose effect relationship was shown [48]
N/A
(n=2)
Decreased RT,
but no decrease in
accuracy [23]
Found
evidence of impairment with most impairment related to
attention and RT [24]
(n=1)
Found suggestive evidence of impairment; for both drugs, studies found impairment in attention, psychomotor skills
, reaction test,
and visual
functions ; dose-effect relationship was observed for both drugs
[48]
(n=1)
Impairing potential in opioid-naïve subjects [24]
RT = Reaction Time
18Slide19
Q1b: Stimulants & Indirect Measures
19
Amphetamines
Methamphetamine
Lisdexamfetamine
Methylphenidate
Original Research Articles
(n=4)
10 mg d-amphetamine improved driving performance; 40 mg improved
car-crossing RT;
doesn’t compensate for fatigue [41]
Enhanced performance after d-amphetamine [42]
No evidence of impairment; improved perceptual speed
& RT [43
]
Performed better on simulator, but not significant [44
]
(n=1)
No evidence of impairment on simulator tasks; improved performance on various simulator tasks [43]
(n=2)
Improved performance on various tasks in young drivers with ADHD
[*39,
*
40
]
*
Two studies used same data set
(n=2)
Improved performance on various driving simulator tasks
[38,
45
]
Systematic Reviews
(n=1)
Positive effects and negative effects observed [23]
(n=1)
Positive effects and negative effects observed [23]
N/A
(n=1)
Improved driver performance in adults with ADHD [46]
RT= Reaction
timeSlide20
Q1b ConclusionsThere is moderate evidence that licit use of opioids negatively impacts indirect measures of driver performance.
Studies generally found indicators of impairment, especially for drug-naïve 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, where these tests were included, findings tended not to be significant. Findings vary across drug and dose
.
20Slide21
Q1b ConclusionsThere 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.
The handful of relevant studies generally found 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.
21Slide22
Q1b ConclusionsThere is moderate evidence that licit use of stimulants has minimal or positive indirect measures of driver performance among drivers taking low doses of stimulants.
The handful of relevant studies generally 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.
Results were mixed as to whether stimulants can help to counter the effects of sleep deprivation.
22Slide23
Research Question 2Are 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=1423Slide24
Q2: Serum Levels
Serum Levels
Original Research Articles
Systematic
Reviews
(n= 10 )
Measuring results via serum levels is largely in concordance with measurements done other ways [8,30,33,36,41,43,44]
Found
three additional significant results for codeine using serum levels [26]
(n=4)
Serum levels are positively associated with impairment [19, 23]
One
out of three studies reviewed linked blood morphine levels to cognitive deficits [47]
Evidence
of concentration relationship for some opioids, but not morphine [48]
24Slide25
Q2 Conclusions
There is moderate evidence that the effects of opioids and stimulants are measureable by serum levels. Findings were generally consistent 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.
25Slide26
Research Question 3
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)?Evidence base n=19
26Slide27
Q3: Stable Use
Stable Use
Original Research Articles
Systematic Reviews
(n=9)
No elevated risk
[28, 30, 45]
Mixed results
[32,
33
]
Impairment, but inconclusive due to potential confounding factor of medical conditions [31]
No significant
risk of road trauma
among
new
opioid
users
[13]
Higher risk of accident for new opioid users than chronic users , but not significant [16]
Increased risk after beginning medication, but risk decreased over time; time of decrease to non-significance varies among drugs [11]
(n=7)
Impairing effect from first-time opioid use [19]
Impairment for long-term opioid use [
23,
47
]
No difference in motor vehicle accidents or violations for stable-use opioid patients; no cognitive or psychomotor impairment
[20, 25]
Psychomotor impairment for chronic pain, stable-use morphine patients; no performance difference in stable-use and patients with similar diseases [48]
Increased crash risk for methadone maintained patients; cognitive & psychomotor impairments [24]
No impairment for first-time stimulant use [19]
Cognitive & psychomotor impairment with chronic amphetamine use; impairment correlated with severity or duration of use [23
]
27Slide28
Q3: Drug Interactions
Drug Interactions
Original Research Articles
Systematic
Reviews
(n=4
)
No difference in performance for two
doses of codeine/
paracetamol
compared to placebo [26]
Impairment on tracking test and divided attention task after oxycodone/
paracetamol
dose [38]
Increased risk of crash for the first four weeks of use of compound analgesic preparations containing acetaminophen and an opioid [11]
Elevated risk across a variety of conditions for drivers fulfilling a prescription for codeine, but dropped to non-significant when co-prescriptions were excluded [1]
(n=1)
No conclusions; insufficient data [19]
28Slide29
Q3 ConclusionsThe 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.
29Slide30
Q3 ConclusionsThere 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.
30Slide31
Q3 Conclusions
The evidence pertaining to whether chronic use of stimulants impacts driving or driving related skills is unacceptably weak. A limited evidence base makes it difficult to draw conclusions on this topic.31Slide32
Conclusion32Slide33
Overall ConclusionsModerate evidence to support the contention that licit use of opioids increases the risk of a motor vehicle crash
Weak evidence to support the contention that licit use of stimulants increases the risk of a motor vehicle crashModerate evidence that licit use of opioids negatively impacts indirect measures of driver performanceWeak evidence that licit use of stimulants positively impacts indirect measures of driver performance among drivers with ADHD Moderate evidence that licit use of stimulants has minimal or positive indirect measures of driver performance among drivers taking low doses of stimulants
33Slide34
Overall ConclusionsModerate evidence that the effects of opioids and stimulants are measureable by serum levelsUnacceptably weak evidence of Schedule II opioid and stimulant’s interactions with other Schedule II or prescription medications
Moderate evidence that stable use of Schedule II opioids is associated with reduced negative impacts on driving and driving related skillsUnacceptably weak evidence of chronic use of stimulants’ impact on driving or driving related skills
34