The influence of THC:CBD oromucosal spray on driving ability in patients with multiple sclerosis‐related spasticity

Abstract Background Driving ability is a key function for the majority of patients with multiple sclerosis (MS) to help maintain daily interactions. Both physical and cognitive disability, as well as treatments, may affect the ability to drive. Spasticity is a common symptom associated with MS, and it may affect driving performance either directly or via the medications used to treat it. In this article, we review the evidence relating the antispasticity medicine, Δ9‐tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex®), and its potential impact on driving performance. Methods Articles were identified by searching PubMed from 1/1/2000 to 30/6/2017 using a specified list of search terms. The articles identified using these search terms were augmented with relevant references from these papers and other articles known to the authors. Results The results from THC:CBD oromucosal spray driving studies and real‐world registries did not show any evidence of an increase in motor vehicle accidents associated with THC:CBD oromucosal spray. The majority of patients reported an improvement in driving ability after starting THC:CBD oromucosal spray, and it was speculated that this may be related to reduced spasticity and/or better cognitive function. It should be noted that THC blood levels are significantly lower than the levels associated with recreational use of herbal cannabis. Conclusions THC:CBD oromucosal spray was shown not to impair driving performance. However, periodic assessment of patients with MS driving ability is recommended, especially after relapses and changes in treatment. Blood THC measurements might be above authorized thresholds for some countries following administration of THC:CBD oromucosal spray, thus specific knowledge of each country's driving regulations and a medical certificate are recommended.


| INTRODUC TI ON
Multiple sclerosis (MS) is a chronic, autoimmune disease caused by inflammation and neurodegeneration which is associated with a wide spectrum of central nervous system symptoms. The disease onset is usually in young adulthood, and common symptoms include fatigue, numbness, tingling, muscle spasticity, decreased cognition, and problems with balance and vision, as well as with bowel and bladder function. Commonly associated symptoms are physical and mental health comorbidities including back pain, arthritis, anxiety, sleep disorders, and depression (Kister et al., 2013;Pugliatti et al., 2006). MS has a significant negative impact on the patient's quality of life (QoL) compared with the general population (Lerdal, Celius, & Moum, 2003;McCabe & McKern, 2002;Murphy, Confavreux, & Haas, 1998).
The chronic, progressive course of MS is associated with physical (muscle paresis and spasticity), sensory (visual and auditory) symptoms, cognitive decline, and psychological impairments that may adversely affect functional independence in terms of activities associated with daily living, including interaction with family and friends, social activities, and ability to work (Freidel et al., 2015;Ryan et al., 2009). Mobility is an important component of functional independence, and the ability to drive a car is often integral to independence, social interactions, and activities of daily living such as access to work, family, shopping, and health care (Rapport, Hanks, & Bryer, 2006). Consequently, cessation of driving has the potential to markedly reduce the QoL in patients with

MS.
Most research examining fitness to drive among persons with neurological impairment has focused on resumption of driving following an acute event, such as traumatic brain injuries (TBI) or stroke (Coleman et al., 2002;Schanke & Sundet, 2000). The course of MS is chronic/progressive albeit often with a number of acute episodes (relapses); therefore, factors related to TBI and stroke associated with fitness to drive may not be generalizable to the MS population.
One study found that cognitive problems, awareness of deficit, and social influences on driving outcomes all played a key role in determining fitness to drive (Ryan et al., 2009). In this study, the majority of patients with MS continued to drive and had better neuropsychological functioning and awareness of deficits than nondrivers.
Drivers unaware of their deficits perceived less need to develop compensatory behaviors, drove more, and had more driving-related accidents. Importantly, the incidence of driving accidents was no different in patients with MS with normal cognition compared with healthy controls (Ryan et al., 2009).
In addition to disease-related changes affecting driving ability, treatment-related issues (mainly medication-related) may also be important. As a group, patients with MS are treated with a multitude of drugs to manage their disease and its symptoms. These include disease-modifying drugs, corticosteroids, and numerous agents to manage symptoms such as anxiety, depression, fatigue, pain, sleep disorders, bladder problems, and spasticity (Coclitu, Constantinescu, & Tanasescu, 2016;Vermersch, 2015).
The aim of the current review was to investigate factors pertaining to the use of the cannabinoid-based medicine oromucosal Δ 9 -tetrahydrocannabinol:cannabidiol [THC:CBD (Sativex ® )] in patients with MS spasticity (MSS) to ascertain its impact on driving ability. Therefore, available data from observational studies and driving tests with THC:CBD oromucosal spray will be evaluated.

| S E ARCH S TR ATEGY
References for this review were identified by searching PubMed from 1 January 2000 to 30 June 2017. The terms "cannabinoids," "Sativex," and "tetrahydrocannabinol"; "cannabidiol," "multiple sclerosis," and "spasticity" were combined with the terms "driving ability," "blood levels," and "traffic accidents". Articles identified using these search terms were augmented with concept-related references known to the authors and others identified in the introduction/discussion sections from all identified papers.

| MULTIPLE SCLEROS IS AND DRIVING
Patients with MS are more likely to be involved in motor vehicle accidents than people without MS (Knecht, 1977;Ling, 2002). In particular, patients with MS with cognitive impairment have a higher incidence of accidents compared with controls and patients with MS without cognitive impairment (Badenes et al., 2014;Schultheis, Garay, Millis, & Deluca, 2002). Various authors suggest that patients with MS should undergo frequent medical assessments and/or driving tests to retain their driving licenses given the progressive nature of the disease (Badenes et al., 2014;Knecht, 1977;Küst & Dettmers, 2014). During driving simulation testing, patients with relapsing-remitting MS had an increased number of accidents and concentration faults compared with healthy controls (Kotterba, Orth, Eren, Fangerau, & Sindern, 2003). Factors impacting driving skills included motor symptoms (weakness, coordination difficulties, paresis, and spasticity), visual and auditory disturbances, and cognitive deficits and depression (Marcotte et al., 2008). The most common cognitive deficits in MS are reduced attention, memory, and psychomotor speed, even early in the disease course (Landro, Sletvold, & Celius, 2000). A study examining the effects of cognitive dysfunction and spasticity on driving ability in patients with MS (n = 17) and healthy controls (n = 14) demonstrated that patients with MS exhibited great variability in driving simulation tests (Marcotte et al., 2008). In a multivariate model, cognitive function was the strongest predictor of difficulty maintaining lane position during a divided attention task and poorer response time to lead car speed changes, while spasticity was associated with reductions in accuracy of tracking the lead car movements and speed maintenance. One study showed that patients with MS who were unaware of their cognitive and physical deficits were less likely to engage in compensatory behaviors and were thus at greater risk of driving-related accidents (Ryan et al., 2009).
The impact of MS treatments on driving ability has not been well studied. Searches for information regarding disease-modifying drugs revealed no references assessing their effects on driving ability. Regarding symptomatic therapy, one small study with intrathecal baclofen for a mean duration of 22 months reported improvement in driving ability in three of four patients and deterioration in the fourth patient (Jagatsinh, 2009). Three studies with THC:CBD oromucosal spray are reported separately below.

| DRUG S AND DRIVING : G ENER AL LEG AL ISSUE S AND LIMITS
According to World Health Organization (WHO) statistics, approximately 1.25 million people died from road traffic injuries in 2013, a 13% increase from 2000, and road traffic injuries are the main cause of death for people aged 15-29 years (World Health Organization, 2015). In an extensive review of driving under the influence of illicit substances of abuse, medications, or alcohol, 5%-25% of incidents involved drivers who tested positive for drugs (illicit substances of abuse or medications, excluding alcohol). It was noted that the drugs detected generally reflected usage patterns in the community (Kelly, Darke, & Ross, 2004), and polydrug usage was commonly detected.
In some countries, it is illegal to drive after the intake of approved medicines if they impair the ability to drive. In other countries, the governments specifically mention drugs such as amphetamines, benzodiazepines (clonazepam, diazepam, flunitrazepam, lorazepam, oxazepam, and temazepam), methadone, and opioids (morphine, codeine, tramadol, and fentanyl) (GOV. UK, 2017a,b). For most of the substances, which are viewed to be of higher risk for causing motor accidents, threshold blood limits have been defined. Levels exceeding these are considered to be a risk to road safety (Table 1)  Illicit drugs usually have zero tolerance. The UK applies this approach to eight of the most commonly used illicit drugs and sets threshold levels for these compounds specifically to rule out claims of accidental exposure (Table 1)

| C ANNAB IS AND C ANNAB INOIDS AND DRIVING
Worldwide herbal cannabis is the most widely used illicit substance   (Cofield et al., 2017).
Of note are the findings of an international working group that reported that acute herbal cannabis usage is associated with a significantly elevated risk of motor vehicle accidents (Asbridge et al., 2012;Rogeberg & Elvik, 2016). There are three main approaches for assessing whether a driver can drive under the influence of herbal cannabis: 1 Impairment-based (effect-based): assessment of the driver to perform certain tasks (the disadvantage is that there is no universally accepted methodology); 2 "Per se" laws which set a legal limit for the level of THC or its metabolites in the body (blood and saliva); 3 Zero tolerance a version of "per se", but the legal limit is set at zero.
Due to the difficulties of assessing the impairment, and the limitations with respect to zero tolerance legislation, the main focus by most national traffic authorities has been to specify legal limits for THC (Wong, Brady, & Li, 2014). Table 2 shows current legal limits for THC and alcohol in 10 European countries; four of these countries have a zero tolerance for THC.
The knowledge of THC from recreational herbal cannabis and driver impairment is also important in the case of persons being treated with medicinal cannabinoids medications. Extrapolation of epidemiological and experimental studies has often been used to ascertain the role of THC in these situations (Grotenhermen et al., 2007;Ramaekers, Berghaus, van Laar, & Drummer, 2004).
Epidemiological studies clearly show an association between more frequent herbal cannabis use, driving within one hour of recreational cannabis smoking, and increased blood THC concentrations with an increased risk of motor vehicle accidents (Hartman & Huestis, 2013). In a case-control study in Australia, drivers with measurable blood THC levels were significantly more likely to be involved in fatal road crashes than drug-free drivers (OR 2.7), and for drivers with a THC level ≥5 μg/L, the risk was even greater (OR 6.6) . Likewise, meta-analyses of TA B L E 2 Legal Δ 9 -tetrahydrocannabinol (THC) and alcohol limits in Europe epidemiological studies also confirmed an increased risk of motor vehicle accidents following acute cannabis use (Li et al., 2012;Rogeberg & Elvik, 2016).
Experimental studies have been used to evaluate the effects of THC on cognitive function and driving ability and a review of more recent studies found that drivers under the influence of THC attempt to compensate by driving more slowly, but increasing the complexity of the tasks performed reduced their ability to maintain control (Hartman & Huestis, 2013).

| Pivotal clinical trials program for THC:CBD oromucosal spray
The first phase 3 clinical trial findings (Collin et al., 2007(Collin et al., , 2010 led the way to an enriched enrollment design study in which only those participants who demonstrated responsiveness to THC:CBD oromucosal spray were eligible for randomization (Novotna et al., 2011). During an initial single-blind 4-week trial,

| THC:CBD pharmacokinetics
Determining the pharmacokinetic (PK) properties of THC following administration of THC:CBD oromucosal spray is important to help us better understand whether the product may affect cognitive function and driving ability.
To investigate the PK of THC:CBD oromucosal spray, 24 healthy male subjects were divided into three groups and received single doses of multiple consecutive sprays: two sprays (5.4 mg THC, n = 6); four sprays (10.8 mg THC, n = 12); and eight sprays (21.6 mg THC, n = 6) ( Figure 1) (Stott, White, Wright, Wilbraham, & Guy, 2013). It should be noted that THC:CBD oromucosal spray administration in daily practice, according to the approved label, states that the required sprays (usually 6-7/day on average) should be spread throughout the day according to individual response and tolerability and that there should be 15 min between individual sprays. This was followed by a multiple-dose study in which the same dosages were taken once daily for nine days. The main THC PK parameters are summarized in Table 3 (Stott et al., 2013). In a second study, equivalent doses of THC (approximately 5 mg and 15 mg) administered as THC:CBD oromucosal spray or as oral synthetic THC resulted in similar PK profiles with no clinically relevant differences between them (Karschner, Darwin, Goodwin, Wright, & Huestis, 2011). This indicates that CBD does not materially impact the PK of THC and, therefore, PK changes do not explain its modulation of THCs psychological effects (Karschner et al., 2011). Importantly, in both of these studies, the THC plasma levels were magnitudes lower than levels reported after smoking herbal cannabis (Huestis & Cone, 2004;Huestis, Henningfield, & Cone, 1992). For example, smoking cannabis with a standardized THC content of 33.8 mg resulted in a C max of 162.2 μg/L and t max of 9 min (Huestis & Cone, 2004), while with THC:CBD oromucosal spray, a C max of 5.4 μg/L and t max of 60 min were observed after a dose of eight sprays in a row (21.6 mg THC) ( Table 4). Significantly lower C max values were recorded after lower dosages of THC:CBD oromucosal sprays, while t max was between 60 and 90 min ( Table 3). The markedly slower delivery and reduced exposure of THC following oromucosal delivery are reassuring and almost certainly explain the very low propensity for psychological effects / abuse. The authors speculated that the improvement in driving ability may be related to less spasticity and/or better cognitive function (Etges et al., 2016).

| THC:CBD oromucosal spray and driving: realworld data/pharmacovigilance
In another long-term prospective observational study that was performed in Spain, driving ability was included as a possible AE of special interest in patients with moderate-to-severe resistant MSrelated spasticity treated with THC:CBD oromucosal spray (Oreja-Guevara, 2015). Safety evaluations were performed after 6 and 12 months' exposure to THC:CBD oromucosal spray. During the course of this study, 93% of patients rated their driving ability as not changed/not reported/not relevant, while 5% rated it as improved, and 1% as deteriorated (Figure 2b).
The specific impact of THC:CBD oromucosal spray treatment on driving ability was investigated in a formal ad hoc observational study in patients with moderate-to-severe resistant MS spasticity in Germany (Freidel et al., 2015).  TA B L E 4 Pharmacokinetic parameters for THC:CBD oromucosal spray (Sativex), for vaporized THC extract and smoked cannabis (Huestis et al., 1992;Summary of Product Characteristics, Sativex Oromucosal Spray, 2017) F I G U R E 2 Change in driving ability in patients with MS spasticity treated with THC:CBD and who were able to drive when included onto an observational product registry in Germany, Switzerland, and the UK (a) (Etges et al., 2016), or an observational study in Spain (b) (Oreja-Guevara, 2015). (a) Product registry (Germany, Switzerland, and the UK; n = 387). (b) Observational study data, Spain (n = 77) to loss of independence, poorer relations with family and friends, and reduced social activity (Rapport et al., 2006). In individuals with MS, research has shown that driving performance may be negatively affected by the disease. For example, recent studies show that both cognitive problems and spasticity (muscle stiffness or spasms) affect driving performance, putting the person at an increased risk of a motor vehicle accident (Niewoehner & Thomas, 2017). Another important consideration is that people with MS may be taking several medications to manage their MS and its associated symptoms (spasticity, mood changes, bladder problems, walking problems, and/or pain). It is imperative that the effects of these treatments on factors that could influence driving performance, such as wakefulness, concentration, coordination, and reaction times, are clearly understood.

| D ISCUSS I ON
In this article, we review the evidence for THC:CBD oromuco- Oromucosal Spray, 2017). The results from the studies and registries reviewed herein did not find any evidence of an increase in motor vehicle accidents associated with THC:CBD oromucosal spray in patients with MS. Furthermore, a majority of patients reported an improvement in driving ability after starting treatment with THC:CBD oromucosal spray, and the authors speculated that this may be related to less spasticity and/or better cognitive function (Etges et al., 2016).
The risk to people treated with THC:CBD oromucosal spray of failing a roadside drugs' test for THC is an issue which is not so easy to respond to. Based on PK data, the answer is dose-(number of sprays) and time-related. The threshold level in the majority of European countries is approximately 1-2 μg/L (Table 2). After nine consecutive days of administration of two sprays of THC:CBD oromucosal spray (containing 5.4 mg THC), the C max of THC was 1.4 μg/L and occurred approximately 1 hr after administration (Etges et al., 2015). So, at this double the standard single spray administration level, persons using THC:CBD oromucosal spray would likely fail a 1 μg/ml THC threshold roadside drugs test for a certain period following administration. However, interpersonal variability might be relevant.
Impairment is used in some jurisdictions to determine the individual's ability to drive. However, based on the current literature, THC blood levels associated with impairment are not entirely clear (Asbridge et al., 2012;Kelly et al., 2004;Wong et al., 2014). Again, this is probably as a result of intersubject variability. In addition, it has been suggested that persons using compounds that impair risk may try to overcome such impairment through compensating behaviors such as driving more slowly and avoiding high-risk situations (Kelly et al., 2004). These are all considerations for physicians treating patients with MS and who may need to make a decision regarding driving suitability. While physicians were generally good at making such decisions, a small proportion of patients with MS (not on THC:CBD oromucosal spray) who were allowed to drive failed an on-road assessment, mainly for visual reasons (Ranchet, Akinwuntan, Tant, Neal, & Devos, 2015). Even though THC:CBD oromucosal spray can result in dose-related levels of THC above the legal threshold for a number of countries, there is no evidence that it is associated with further impairment of driving performance in patients with MS based on a significant amount of postmarketing safety data available. This may be related to the slower delivery of the drug observed in PK studies.

| CON CLUS IONS
MS is a chronic neurological disease which is associated with a spectrum of symptoms that may impact the functional status, overall wellbeing, and QoL of the individual. The disease and its treatments have the potential to impair driving ability, an ability that most affected patients will want to retain as long as possible. The cannabinoid-based medication THC:CBD oromucosal spray can be successfully prescribed to patients with MS to help relieve spasticity and associated symptoms. It has not been shown to impair driving if adverse events such as somnolence and dizziness are not present. However, periodic assessment of the MS patient's driving ability is recommended, especially after relapses and treatment changes. Blood THC measurements might record levels above the authorized thresholds for some countries at different time points after intake. Recommendations regarding driving after administration of THC:CBD oromucosal spray need to be considered on a country-by-country basis, to adapt to specific laws. The EU label states that patients should not drive, operate machinery, or engage in any hazardous activity if they are experiencing any significant CNS effects such as dizziness or somnolence.
THC blood levels after administration of THC:CBD oromucosal spray will be under the allowed threshold a few hours after intake in most cases (except when the threshold is "zero"). However, individual variability does not guarantee this. Having a medical certificate confirming the medical prescription of THC containing treatment and the absence of driving impairment while on the medication is therefore recommended. The traffic authorities of countries where the medical prescription of a THC containing medicine is permitted and, as long as physician reports lack of impairment in driving ability, should be asked to make specific considerations for such individuals in their regulations. This is currently the case in Austria, Denmark, Finland, Germany, and Sweden.

ACK N OWLED G M ENTS
Editorial support in the preparation of the manuscript was provided by Dr Steve Clissold (Content Ed Net, Spain) which was funded by Almirall SA.

CO N FLI C T O F I NTE R E S T
EGC has received personal compensation for serving on scientific advisory boards for Almirall, Biogen, Merck, Novartis, Genzyme, and Teva and has received speaker honoraria from Biogen, Genzyme, Novartis, Merck, and Teva, and her department has received unrestricted research grants from Novartis and Genzyme.