Side effect of scopolamine

Contents

Scopolamine

Scopolamine is a prescription drug used to treat Parkinson’s disease, muscle spasms, irritable bowel syndrome, and the nausea, vomiting, and dizziness that often accompanies motion sickness.

While Scopace, the brand-name tablet form of scopolamine, was discontinued in 2011, a few compounding pharmacies make replicas of it.

Under the name Transderm-Scop, made by Novartis, scopolamine is also available as a behind-the-ear skin patch worn to curb seasickness and the vomiting associated with some anesthetics and surgical painkillers.

Scopolamine belongs to a class of drugs called anticholinergics. These work by blocking the activity of the neurotransmitter acetycholine, which stimulates the part of the brain that triggers nausea and vomiting, as well as involuntary muscle movement in the lungs, and the gastrointestinal and urinary tracts.

Approved by the Food and Drug Administration (FDA) in 1979, scopolamine has also been prescribed “off label” for asthma, depression, as a smoking-cessation remedy, and to relieve the nausea that accompanies chemotherapy.

Scopolamine Abuse

As an alkaloid derived from the belladonna plant, scopolamine has the potential for abuse.

Among prisoners who smoked crushed scopolamine tablets, hallucinations were the most common neurological effect, with amnesia not far behind, according to a study in the journal Substance Use & Misuse.

Scopolamine has also been used by criminals to sedate victims, mainly in Colombia, where the tree from which it derives proliferates.

Slipped into drinks, on food, or sprinkled on pieces of paper, it renders its victims so submissive that they have been known to empty their bank accounts and help thieves rob their homes, reported Vice News in the documentary “The Most Dangerous Drug in the World.”

Scopolamine Warnings

Even in therapeutic doses, scopolamine comes with serious warnings.

Although rare, in regular doses it can cause confusion, agitation, rambling speech, hallucinations, and paranoia.

It can produce allergic reactions, signaled by difficulty breathing, constriction of the throat, swelling of the lips, tongue, or face, and hives. Before taking scopolamine, discuss any allergies you have with your doctor.

You should also talk to your doctor if you have glaucoma, kidney disease, liver disease, heart disease, or congestive heart failure. Scopolamine is usually not recommended if you have these conditions.

If you have difficulty urinating because of an enlarged prostate or a blockage in the bladder, scopolamine can aggravate this symptom.

Since scopolamine can make the body more sensitive to heat, you need to take extra care outdoors during hot weather, according to the Consumer Health Information Corp., or when in a hot tub or sauna.

Scopolamine and Pregnancy

Scopolamine is in FDA Pregnancy Category C, meaning its risk to the fetus is unknown, so talk to your doctor if you are pregnant or trying to get pregnant, before taking scopolamine.

While there are no human studies to document the safety of scopolamine while breastfeeding, the American Academy of Pediatrics considers scopolamine to be compatible with breastfeeding.

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Why an M1 Antagonist Could Be a More Selective Model for Memory Impairment than Scopolamine

Since the early studies of Deutsch (1), the non-selective muscarinic receptor antagonist scopolamine has been used as a drug that impairs memory performance in man. The notion that scopolamine could be used as a pharmacological model of age-associated memory impairment and dementia further strengthened the cholinergic hypothesis of geriatric memory dysfunction by Bartus et al. (2). Since then, a vast amount of studies applied this model to induce memory impairments in young healthy subjects to model age-related memory disorders. At present, scopolamine is still considered to be the best model for inducing cognitive impairments in healthy subjects (3). Scopolamine is therefore used as a pharmacological model to test novel cognition-enhancing drugs in animals and in humans . In clinical trials, scopolamine is in particular being used as a model for AD in which novel cognition-enhancing drugs are tested (see https://ClinicalTrials.gov).

Further efforts have been made to compare human and animal data with scopolamine to further validate the scopolamine as a model of cognitive impairments. For example, comparable tests were developed for humans and animals to allow cross-species comparison . Another effort is comparing scopolamine effects on brain imaging parameters (11, 12). These studies reveal great cross-species similarities in the effects of scopolamine in comparable cognitive tasks in humans and animals, and that the effects on central blood flow is also comparable. These studies have resulted in a huge database in which the effects of scopolamine on cognitive and non-cognitive functions have been documented. This also relates to doses and routes of administration. Furthermore, interactions with various other drugs (also non-cholinergic) have been documented, which supports the notion of drug interactions in memory functions. Taken together, scopolamine is considered as a golden standard for cholinergic deficits and the existing data were used as a reference for evaluating novel cognition-enhancing drugs.

Although scopolamine has this established (gold standard) status, there are also some important issues related with this drug. A first point is that scopolamine is binding to both peripheral and central muscarinic receptors . Thus, scopolamine binds to all five different muscarinic receptors which are located in the brain as well in the peripheral system. This may relate to the various side effects that can occur after administration of scopolamine. Typical side effects are: dry mouth or throat, dizziness, drowsiness, fatigue, nausea, light-headedness, and blurred vision . A careful analytic review on the effects of scopolamine in animals has shown that scopolamine at low doses mainly affects attentional functions and that memory performance is only affected at higher doses . Moreover, at relative low doses, typical side effects (increased omissions and latencies in responding) can be observed in rodents that may have an impact on performance in memory tasks.

In humans, similar effects on sedation have been observed, but it has been suggested that these effects could be dissociated from the effects on memory impairments . Interestingly, these effects seem to be dependent on the route of administration. Thus, intramuscular or intravenous administration has shown robust effects on memory performance (3), accompanied with sedative effects. However, oral administration of scopolamine has resulted in sedative effects but in the absence of memory impairments (15, 16). Interestingly, the effects of intranasal scopolamine have also been investigated on side effects and cognitive performance (17, 18). This generally leads to a faster brain penetration and may have a stronger effect on brain function. Notably, no effects were found on cognition, and only some side effects were reported. However, it could be argued that the dose was too low (0.4 mg) or brain penetration was too fast in order to affect cognitive performance. Unfortunately, no plasma concentrations can be measured after intranasal administration, which makes it difficult comparing this with other routes of administration. Apparently, the effects of scopolamine on sedation are found in most clinical studies, whereas the effects on cognition are reported in fewer studies. Some experimental studies explicitly investigated the relation between sedation and cognition by comparing the effects of scopolamine and benzodiazepines (GABAA agonist). In one study, the effects of scopolamine and lorazepam on cognition and sedation could not be separated (19). However, the effect of scopolamine and lorazepam can be separated on encoding processes, as shown in a repetitive priming paradigm (20). Another study also showed a differential effect of lorazepam and scopolamine on attention and working memory (21). Thus, the effects of benzodiazepines and scopolamine on arousal may be similar, but the effects on cognitive functions can be differentiated if specific tasks are used.

A subsequent study was able to show a one-sided dissociation between sedation and cognitive impairment (22). In this study, the effects of an H1 receptor antagonist (diphenhydramine) were compared with lorazepam and scopolamine. All drugs affected arousal but only scopolamine and lorazepam impaired memory. These findings were supported by the drug effects on EEG measures and indicate that the effects on arousal and memory were not interdependent. Although different studies suggest a differentiation between drug effects on arousal and memory (19, 22), a drug that only impairs cognitive functions and not the arousal state would be preferable. Moreover, this would show a double dissociation between arousal and memory performance (22).

Although the literature has shown robust effects of scopolamine on word learning (episodic memory task), some reported findings may suggest something else. Thus, scopolamine had a larger effect on immediate and delayed recall when presentation rate was fast (i.e., 1 word per 2 s), whereas it had only a marginal effect when presentation rate was 1 word per 5 s (23). The effects of scopolamine on word learning seem to be dependent on the pace of the task, which is related to the presentation time, inter-stimulus interval, and response-stimulus interval. These parameters are of key importance, whether attentional circuits in the brain are triggered. The faster the pace, the more declarative memory performance will become dependent on attentional constraints . Taken together, these findings suggest that the separation between arousal/attention and memory effects may not be easy to establish and require more variation of experimental parameters before this can be demonstrated.

As mentioned earlier, scopolamine is assumed to model the impaired cholinergic neurotransmission in AD. However, more recent studies have also shown other characteristic features of brain dysfunction in AD and the scopolamine model. For example, arterial spin labeled perfusion MRI studies have shown hypoperfusion mainly in the temporal lobe regions of AD patients (25, 26). In contrast, scopolamine has been found to mainly reduce cerebral blood flow in frontal areas (27–29). Although it may be questioned to what extend reduced blood flow in specific brain regions may relate to specific cognitive functions, these data do not support a strong face/predictive validity for scopolamine with respect to brain blood flow and the site of action in the brain. Although the above may caution the use of scopolamine as a model for memory impairment, scopolamine still is the golden standard for this purpose. The main advantage is that this drug is well characterized and there is enormous database to which the effects with new treatments can be compared with. For these reasons, it is obvious that scopolamine still will be used as a drug to induce memory impairments in animals and humans to model aging/AD-related memory dysfunctions.

Interestingly, a more specific cholinergic memory deficit model has been proposed based on selectivity of muscarinic receptors. Both the M1 and M2 receptors have been indicated as relevant for cognition, but most research has focused on the M1 receptor (30). It has been shown that the M1 receptor is more specifically located in cortical and hippocampal structures and that its expression in the body is limited . Moreover, the M1 receptor has been indicated to be related to cognitive deficits in AD (31, 32). Therefore, it has been suggested that blocking the M1 receptor could be regarded as a better model for age-associated and dementia-related memory deficits (13, 33). Biperiden, which is clinically used to reduce motor symptoms in Parkinson’s disease, is a relative selective muscarinic type 1 (M1) antagonist (34), and could be used as a drug to evaluate the effects on memory. Two human studies have shown selective effects of biperiden treatment on memory performance with only limited side effects (35, 36). A noteworthy feature of the postsynaptic M1 receptor is that an antagonist can impair memory performance and that an agonist can improve performance. Thus, the M1 receptor is also considered as a target to improve memory functions (37, 38). Various M1 agonists have been developed as drugs to improve memory performance in dementia and schizophrenia (39). One of the first (orthosteric) M1 agonist that showed efficacy in Alzheimer patients and schizophrenics was xanomeline (40, 41). However, this drug was not very selective for the M1 receptor and associated with dose-limiting side effects and was therefore not further developed. More recently, positive allosteric modulators (PAMs) have been developed which are more selective for the M1 receptor. One study in monkeys showed that an M1 positive allosteric modulator (PAM) improved the performance in an object detour test (42). Another study in humans showed that a PAM of the M1 receptor improved memory functions in a nicotine abstinence model (43). Taken together, the M1 receptor can be regarded as an interesting specific target for memory modulation.

The main mechanism by which M1 receptors can impair or improve memory is obviously via the cholinergic neurotransmission. However, additional mechanisms of action of M1 receptors have been described. For example, an in vitro study showed that blocking the M1 receptor decreases dendritic long-term potentiation (LTP) in the CA1 region of the hippocampus (44). Conversely, activation of the M1 receptors enhances LTP in the hippocampus (45). These effects are mediated by a co-localization of M1 and NMDA receptors and that activation of M1 receptors leads to enhanced NMDA receptor currents (46). This bidirectional modulation of LTP by M1 receptor modulation supports the notion that, aside from a cholinergic mechanism, LTP is also involved in the modulating the memory effects. It should be noted that the M1 receptor is also located in medium spiny neurons, where they are involved in neuronal plasticity and involved in motor functions (47). There are also studies showing that blocking the M1 receptors may affect more complex motor behavior . Actually, the M1 receptor antagonist biperiden was developed for this purpose. Although modulation of the M1 receptor in this structure may contribute to the behavioral effects of drugs that affect this receptor, it has been shown that the strongest effects of allosteric agonist were most pronounced in the hippocampus and to a lesser extend in the striatum (50). This may suggest that M1 drugs predominantly affect hippocampal-related functions. Along this line, the prescription of biperiden reports that amongst its side effects is memory loss. Moreover, this may further support the use of M1 antagonists as a model for selective memory impairment.

In summary, although scopolamine is being used to induce memory impairments in human subjects some aspects of this drug may caution the use of this drug to specifically impair memory performance. M1 antagonism can impair memory more specifically and M1 agonism (more specifically, PAMs) can improve memory. This strongly supports the notion that the M1 receptor is highly relevant and specific for memory. The use of M1 antagonist may offer a good alternative but more data are needed to support this claim.

Author Contributions

AB wrote the paper. AS, JP, and WR commented on earlier versions of the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Transderm Scop

WARNINGS

Included as part of the “PRECAUTIONS” Section

PRECAUTIONS

Acute Angle Closure Glaucoma

The mydriatic effect of scopolamine may cause an increase in intraocular pressure resulting in acute angle closure glaucoma. Monitor intraocular pressure in patients with open angle glaucoma and adjust glaucoma therapy during Transderm Scop use, as needed. Advise patients to immediately remove the transdermal system and contact their healthcare provider if they experience symptoms of acute angle closure glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema).

Neuropsychiatric Adverse Reactions

Psychiatric Adverse Reactions

Scopolamine has been reported to exacerbate psychosis. Other psychiatric reactions have also been reported, including acute toxic psychosis, agitation, speech disorder, hallucinations, paranoia, and delusions . Monitor patients for new or worsening psychiatric symptoms during treatment with Transderm Scop. Also, monitor patients for new or worsening psychiatric symptoms during concomitant treatment with other drugs that are associated with similar psychiatric effects .

Seizures

Seizures and seizure-like activity have been reported in patients receiving scopolamine. Weigh this potential risk against the benefits before prescribing Transderm Scop to patients with a history of seizures, including those receiving anti-epileptic medication or who have risk factors that can lower the seizure threshold.

Cognitive Adverse Reactions

Scopolamine can cause drowsiness, disorientation, and confusion. Discontinue Transderm Scop if signs or symptoms of cognitive impairment develop. Elderly and pediatric patients may be more sensitive to the neurological and psychiatric effects of Transderm Scop. Consider more frequent monitoring during treatment with Transderm Scop in elderly patients . Transderm Scop is not approved for use in pediatric patients .

Hazardous Activities

Transderm Scop may impair the mental and/or physical abilities required for the performance of hazardous tasks such as driving a motor vehicle, operating machinery or participating in underwater sports. Concomitant use of other drugs that cause central nervous system (CNS) adverse reactions (e.g., alcohol, sedatives, hypnotics, opiates, and anxiolytics) or have anticholinergic properties (e.g., other belladonna alkaloids, sedating antihistamines, meclizine, tricyclic antidepressants, and muscle relaxants) may increase this effect . Inform patients not to operate motor vehicles or other dangerous machinery or participate in underwater sports until they are reasonably certain that Transderm Scop does not affect them adversely.

Eclamptic Seizures In Pregnant Women

Eclamptic seizures have been reported in pregnant women with severe preeclampsia soon after injection of intravenous and intramuscular scopolamine . Avoid use of Transderm Scop in patients with severe preeclampsia.

Gastrointestinal And Urinary Disorders

Scopolamine, due to its anticholinergic properties, can decrease gastrointestinal motility and cause urinary retention. Consider more frequent monitoring during treatment with Transderm Scop in patients suspected of having intestinal obstruction, patients with pyloric obstruction or urinary bladder neck obstruction and patients receiving other anticholinergic drugs . Discontinue Transderm Scop in patients who develop difficulty in urination.

Drug Withdrawal/Post-Removal Symptoms

Discontinuation of Transderm Scop, usually after several days of use, may result in withdrawal symptoms, such as disturbances of equilibrium, dizziness, nausea, vomiting, abdominal cramps, sweating, headache, mental confusion, muscle weakness, bradycardia and hypotension. The onset of these symptoms is generally 24 hours or more after the transdermal system has been removed. Instruct patients to seek medical attention if they experience severe symptoms.

Blurred Vision

Scopolamine can cause temporary dilation of the pupils resulting in blurred vision if it comes in contact with the eyes.

Advise patients to wash their hands thoroughly with soap and water and dry their hands immediately after handling the transdermal system .

Magnetic Resonance Imaging (MRI) Skin Burns

Transderm Scop contains an aluminized membrane. Skin burns have been reported at the application site in patients wearing an aluminized transdermal system during an MRI scan. Remove Transderm Scop before undergoing an MRI.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

Administration Instructions

Counsel patients on how to apply and remove the transdermal system :

  • Only wear one transdermal system at any time.
  • Do not cut the transdermal system.
  • Apply the transdermal system to the skin in the postauricular (hairless area behind one ear) area.
  • After the transdermal system is applied on the dry skin behind the ear, wash hands thoroughly with soap and water and dry hands.
  • If the transdermal system becomes displaced, discard the transdermal system, and apply a new transdermal system on the hairless area behind the other ear.
  • Upon removal, fold the used transdermal system in half with the sticky side together, and discard in household trash in a manner that prevents accidental contact or ingestion by children, pets or others.
Patients With Open-Angle Glaucoma

Advise patients with open-angle glaucoma to remove the Transderm Scop transdermal system immediately and contact their healthcare provider if they experience symptoms of acute angle closure glaucoma, including pain and reddening of the eyes, accompanied by dilated pupils, blurred vision and/or seeing halos around lights .

  • Advise patients that psychiatric adverse reactions may occur, especially in patients with a past psychiatric history or in those receiving other drugs also associated with psychiatric effects, and to report to their healthcare provider any new or worsening psychiatric symptoms.
  • Advise patients to discontinue Transderm Scop and contact a healthcare provider immediately if they experience a seizure.
  • Advise patients, especially elderly patients, that cognitive impairment may occur during treatment with Transderm Scop, especially in those receiving other drugs also associated with CNS effects, and to report to their healthcare provider if they develop signs or symptoms of cognitive impairment such as hallucinations, confusion or dizziness.
  • Inform patients not to operate motor vehicles or other dangerous machinery or participate in underwater sports until they are reasonably certain that Transderm Scop does not affect them adversely .
Decreased Gastrointestinal Motility And Urinary Retention

Instruct patients to remove the transdermal system if they develop symptoms of intestinal obstruction (abdominal pain, nausea or vomiting) or any difficulties in urinating .

Inform patients that if they remove the Transderm Scop transdermal system before treatment is complete, withdrawal symptoms may occur and to seek immediate medical care if they develop severe symptoms after removing Transderm Scop .

Inform patients that temporary dilation of the pupils and blurred vision may occur if Transderm Scop comes in contact with the eyes. Instruct patients to wash their hands thoroughly with soap and water immediately after handling the transdermal system .

MRI Skin Burns

Instruct patients to remove the Transderm Scop transdermal system before undergoing an MRI .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No long-term studies in animals have been conducted to evaluate the carcinogenic potential of scopolamine. The mutagenic potential of scopolamine has not been evaluated.

Fertility studies were performed in female rats and revealed no evidence of impaired fertility or harm to the fetus due to scopolamine hydrobromide administered by daily subcutaneous injection. Maternal body weights were reduced in the highest-dose group (plasma level approximately 500 times the level achieved in humans using a transdermal system). However, fertility studies in male animals were not performed.

Use In Specific Populations

Pregnancy

Risk Summary

Available data from observational studies and postmarketing reports with scopolamine use in pregnant women have not identified a drug associated risk of major birth defects, miscarriage, or adverse fetal outcomes. Avoid use of Transderm Scop in pregnant women with severe preeclampsia because eclamptic seizures have been reported after exposure to scopolamine (see Data).

In animal studies, there was no evidence of adverse developmental effects with intravenous administration of scopolamine hydrobromide revealed in rats. Embryotoxicity was observed in rabbits at intravenous doses producing plasma levels approximately 100 times the levels achieved in humans using a transdermal system.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Eclamptic Seizures

In published case reports, two pregnant patients with severe preeclampsia were administered intravenous and intramuscular scopolamine, respectively, and developed eclamptic seizures soon after scopolamine administration .

Animal Data

In animal reproduction studies, when pregnant rats and rabbits received scopolamine hydrobromide by daily intravenous injection, no adverse effects were observed in rats. An embryotoxic effect was observed in rabbits at doses producing plasma levels approximately 100 times the levels achieved in humans using a transdermal system. Scopolamine administered parenterally to rats and rabbits at doses higher than the dose delivered by Transderm Scop did not affect uterine contractions or increase the duration of labor.

Lactation

Scopolamine is present in human milk. There are no available data on the effects of scopolamine on the breastfed infant or the effects on milk production. Because there have been no consistent reports of adverse events in breastfed infants over decades of use, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Transderm Scop and any potential adverse effects on the breastfed child from Transderm Scop or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Pediatric patients are particularly susceptible to the adverse reactions of scopolamine; including mydriasis, hallucinations, amblyopia and drug withdrawal syndrome. Neurologic and psychiatric adverse reactions, such as hallucinations, amblyopia and mydriasis have also been reported.

Geriatric Use

Clinical trials of Transderm Scop did not include sufficient number of subjects aged 65 years and older to determine if they respond differently from younger subjects. In other clinical experience, elderly patients had an increased risk of neurologic and psychiatric adverse reactions, such as hallucinations, confusion, dizziness and drug withdrawal syndrome . Consider more frequent monitoring for CNS adverse reactions during treatment with Transderm Scop in elderly patients .

Renal Or Hepatic Impairment

Transderm Scop has not been studied in patients with renal or hepatic impairment. Consider more frequent monitoring during treatment with Transderm Scop in patients with renal or hepatic impairment because of the increased risk of CNS adverse reactions .

What are the Effects of Mixing Dramamine and Alcohol?

Dramamine is a brand-name motion sickness medicine. Dimenhydrinate—itself a chemical combination of the antihistamine diphenhydramine and a methylxanthine stimulant called 8-chlorotheophylline—comprises the primary active ingredients in Dramamine (original formulation).

Together, these compounds help to alleviate the symptoms associated with motion sickness, such as nausea, dizziness, and vomiting and to offset some of the drowsiness common to this type of treatment.1

What Is Motion Sickness?

Motion sickness is a condition that commonly develops under certain circumstances, such as while boating (especially on choppy waters), sitting on a turbulent flight, or riding in a car on winding roads.

Motion sickness is thought to develop as a result of a mismatch of sensory signals processed by your brain. Your brain receives sensory information from many places, including your eyes, inner ears, joints, and muscles. When the usual processing of these parallel signals is somewhat disrupted—for example, by unusual motion in a car, boat, or plane—you may begin to feel sick.

For example, think about a common scenario that invokes motion sickness: reading in the backseat of the car. Your eyes are looking at something stationary (the book) and you don’t have a clear view of the road (you’re likely looking at the back of the seat in front of you). However, your inner ears send signals to your brain that indicate that you are moving. With these mixed signals, you may start to feel bad quickly. Initially, you may feel slightly uneasy in your stomach, but these feelings can rapidly progress to dizziness and nausea or vomiting.2

While anyone may get motion sick, women (especially those who are pregnant) and children are especially vulnerable.3,4

Have you been drinking?

Some lucky people don’t get motion sickness, but if you do, it can ruin a cruise or sailing trip — even a road trip. You may have tried over-the-counter medications like Dramamine and Bonine, but in the end, preventing motion sickness might best be solved with the help of your doctor.

Here’s what you should know about motion sickness and how to choose the best treatment for you.

How is motion sickness caused?

The most widely held explanation for why some of us experience motion sickness is called the “sensory conflict hypothesis.” Simply put, each person has an internal representation of bodily movement. This internal picture is continuously updated by information your body receives from your eyes, the balance system in your inner ear (aka. the vestibular system), and sensory receptors in your joints and muscles.

Motion sickness occurs when there is a mismatch. The body can’t figure out if it’s moving, the water is moving, or your legs are moving — and it’s not happy. Your brain receives conflicting sensory inputs and the results are nausea and vomiting.

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What’s the best medication to prevent motion sickness?

Scopolamine patches (Transderm Scop) are the best way to prevent nausea associated with motion sickness. They require a prescription, but they’re preferred over popular over-the-counter alternatives.

Scopolamine patches are more effective than the motion sickness antihistamine meclizine (Antivert or Bonine). They’re also just as effective as Dramamine (dimenhydrinate), and unlike Dramamine, they don’t make you sleepy.

How do motion sickness patches work?

Scopolamine is prescribed as a transdermal patch (a patch you put on the skin). This helps make up for the short amount of time scopolamine works when it’s taken by mouth. One patch contains 1.5 mg of scopolamine and is meant to deliver 0.5 mg per day over a three-day period. So you change the patch every three days.

The proposed way that scopolamine patches work is complicated. Basically, they work by helping your body understand its environmental orientation, despite the irregular signals your inner ear might be sending to your brain.

The patch goes behind the ear because that area is highly permeable — it’s the place on your skin where the medication can get through the easiest. That’s also why scopolamine needs to be dosed at a lower quantity to be effective.

Are there any side effects to the motion sickness patch?

Dry mouth is a common complaint, and other side effects include some drowsiness, dilated pupils and rapid heartbeat. Generally though, the patch is very well tolerated.

How much does the motion sickness patch cost?

Transderm Scop is the brand-name version of the generic patch, Scopolamine. It is covered by most insurance plans, often with a moderate co-pay, so it isn’t the most expensive drug out there if you’re insured. However, if you’re paying cash, you could be looking at about $85 for four patches — something to weigh against the drowsy side effects of Dramamine. The generic patches cost about the same out of pocket, but you may be able to find them for as low as $30 for four patches if you shop around.

What doesn’t work for motion sickness?

Ondansetron (Zofran) and the antihistamines cetirizine (Zyrtec) and fexofenadine (Allegra) do not reduce symptoms of motion sickness and should not be used.

Dr O.

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  • Scopolamine Transdermal Patch

    Before using scopolamine patches,

    • tell your doctor and pharmacist if you are allergic to scopolamine, other belladonna alkaloids, any other medications, or any of the ingredients in scopolamine patches. Ask your doctor or pharmacist, check the package label, or check the Medication Guide for a list of the ingredients.
    • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antihistamines such as meclizine (Antivert, Bonine, others); medications for anxiety, irritable bowel disease, motion sickness, pain, Parkinson’s disease, seizures or urinary problems; muscle relaxants; sedatives; sleeping pills; tranquilizers; or tricyclic antidepressants such as desipramine (Norpramin), clomipramine (Anafranil), imipramine (Tofranil), and trimipramine (Surmontil) Many other medications may also interact with scopolamine patch, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
    • tell your doctor if you have angle-closure glaucoma (a condition where the fluid is suddenly blocked and unable to flow out of the eye causing a quick, severe increase in eye pressure which may lead to a loss of vision). Your doctor will probably tell you not to use scopolamine patch.
    • tell your doctor if you have or have ever had open-angle glaucoma (increase in internal eye pressure that damages the optic nerve); seizures; psychotic disorders (conditions that cause difficulty telling the difference between things or ideas that are real and things or ideas that are not real); stomach or intestinal obstruction; difficulty urinating; preeclampsia (condition during pregnancy with increased blood pressure, high protein levels in the urine, or organ problems); or heart, liver, or kidney disease.
    • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while using scopolamine patches, call your doctor immediately.
    • if you are having surgery, including dental surgery, tell the doctor or dentist that you are using scopolamine patches.
    • you should know that scopolamine patch may make you drowsy. Do not drive a car or operate machinery until you know how scopolamine patches will affect you. If you participate in water sports, use caution because this medication can have disorienting effects.
    • talk to your doctor about the safe use of alcoholic beverages while using this medication. Alcohol can make the side effects caused by scopolamine patches worse.
    • talk to your doctor about the risks and benefits of using scopolamine if you are 65 years of age or older. Older adults should not usually use scopolamine because it is not as safe or effective as other medications that can be used to treat the same condition.

    The effect of transdermal scopolamine for the prevention of postoperative nausea and vomiting

    Introduction

    Postoperative nausea and vomiting (PONV) are among the most common complaints from patients and clinicians (Jones et al., 2006; Sood et al., 2007). Prevention and treatment of PONV is a key patient care component capable of alleviating patient discomfort, distress, and dissatisfaction during the postoperative period. PONV per se is a significant complication that may lead to other postoperative adverse events including aspiration, pneumonitis, dehydration, wound dehiscence, acid-base disorders, and electrolyte imbalance, hematoma formation, esophageal rupture, increases in intraocular and/or intracranial pressures, and acute blood pressure elevations (Fabling et al., 2000; Lipp and Kaliappan, 2007; Feng et al., 2009). According to Society of Ambulatory Anesthesia (SAMBA) Consensus Guidelines for the Management of PONV, the incidence of PONV is between 20–30% among all patients undergoing surgery. With no prophylactic therapy, PONV occurs in as many as 70–80% of high-risk patients undergoing surgery (Gan et al., 2014). Three categories of baseline risk factors: patient-specific, anesthetic, and surgical, are independent predictors of PONV, and may be helpful in selecting the right candidates for prophylaxis. The most prevalent patient and anesthesia related risk factors for PONV are female gender, non-smoking status, postoperative opioid consumption, and a history of PONV/postoperative discharge nausea and vomiting (PDNV) or motion sickness (Apfel et al., 1999). Each factor has a punctuation value of 1, which, when added, will equal 0–4. When 0, 1, 2, 3, or 4 of the above mentioned independent predictors are present; the corresponding risk for PONV is approximately 10, 20, 40, 60, or 80%, respectively (Gan and Habib, 2003; Gan et al., 2014). Presence of a single risk factor corresponds to a 20% risk of PONV, while combination of all the risk factors will be related to an 80% chance of PONV (Apfel et al., 1999). The SAMBA Consensus Guidelines for the Management of PONV include assessing the patient’s risk, reducing the baseline risk factors, and providing prophylactic treatment. The current (Gan et al., 2014) prophylactic therapy recommendations for PONV management stated in the SAMBA guidelines should start with monotherapy and patients at moderate to high risk, a combination of antiemetic medication should be considered. Consequently, if rescue medication is required, the antiemetic drug chosen should be from a different therapeutic class and administration mode than the drug used for prophylaxis. Considering the increasing rate of outpatient surgeries, long-lasting prophylactic antiemetic therapeutic efforts may be beneficial for postoperative patient care and improve the outcomes. Scopolamine is a long-acting prophylactic antiemetic (72 h) approved in 1979 by the Food and Drug Administration (FDA; Apfel et al., 2010) as a method of preventing motion sickness and, since 2001 – for prevention of PONV. In outpatient surgical patients, PDNV usually remains unrecorded because of early discharge, despite the fact that the patients report this complication as the most undesirable postoperative event. Thus, taking into account the beneficial effects of scopolamine, its favorable pharmacokinetic and pharmacodynamic profile, and importance of PONV prophylaxis, transdermal delivery system (TDS) may become a strong candidate as a first-line prophylactic medication in perioperative care (Pergolizzi et al., 2012).

    Overview of Scopolamine

    Scopolamine is a non-polar, belladonna alkaloid, α-(hydroxymethyl) benzeneacetic acid 9-methyl-3-oxa-9-azatricyclo non-7-yl ester. The empirical formula is C17H21NO4 and its structural formula is a tertiary amine L-(2)-scopolamine. It is a viscous liquid that has a molecular weight of 303.35 and a pKa of 7.55–7.81. Scopolamine is a high-affinity selective competitive antagonist of G protein-coupled muscarinic receptor for acetylcholine with both, peripheral and central antimuscarinic effects, including sedative, antiemetic, and amnesic action (Pergolizzi et al., 2011). It acts on the central nervous system (CNS) by blocking cholinergic transmission from vestibular nuclei to higher CNS centers and from the reticular formation to the vomiting center (Renner et al., 2005; Package Insert, 2006). Scopolamine is available as an oral tablet, injectable solution, and TDS. However, the oral and/or parenteral routes of administration are rarely used due to pronounced dose-dependent side effects (excessive sedation, agitation, hallucinations, vertigo, dry mouth, and drowsiness) and a short plasma half-life.

    Transdermal Scopolamine: Pharmacokinetics and Pharmacodynamic Properties

    Transdermal delivery system (TDS) delivery system (patch) functions as a long-acting prophylactic antiemetic (72 h). It is a 0.2 mm thick and 2.5 cm2 film, with four layers (Pergolizzi et al., 2012). The first layer of the patch is a tancolored aluminized polyester film. The second layer is a drug reservoir mixture of scopolamine, light mineral oil, and polyisobutylene. The third layer represents a dose delivery rate controlling microporous polypropylene membrane, and the fourth layer is an adhesive surface formulation of mineral oil, polyisobutylene, and priming dose of scopolamine applied directly to the skin (Nachum et al., 2006; Package Insert, 2006). Only the active drug scopolamine is being released from the delivery system during the TDS application. This patch is designed for continuous release of scopolamine following application to the skin, with the highest permeation rate in the postauricular (mastoid) area, and the lowest permeation in the thigh, higher in the forearm, and still higher in the stomach, chest and back (Pergolizzi et al., 2011).

    The TDS contains 1.5 mg of the drug in a reservoir designed to provide a continuous slow release of scopolamine through intact skin during the first 72 h of patch application (Pergolizzi et al., 2011). The priming dose of scopolamine (140 μg), when applied to the post-auricular area, increases the plasma detectable levels are reached within 4 h with a peak level at 24 h. The rate of scopolamine release after the patch application equals 0.5 mg/day of scopolamine over a 3 days period. The average plasma concentration produced is 87 pg/mL for free scopolamine and 354 pg/mL for total scopolamine (free fraction and conjugated drug; Package Insert, 2006). After removal of the used system, plasma scopolamine levels decrease gradually with an elimination half-life of 9.5 h (Pergolizzi et al., 2011). Upon absorption, scopolamine is mostly bound to plasma proteins and undergoes an almost complete hepatic elimination via hepatic conjugation with subsequent urinary excretion of hydrophilic metabolites. Less than 5% of scopolamine is excreted unchanged (Renner et al., 2005; Nachum et al., 2006). Like atropine, scopolamine acts as a non-specific competitive antagonist of acetylcholine at muscarinic receptors. Due to receptor sensitivity, the inhibition of salivation (M3 receptors) can be reached at lower doses, whereas much higher doses are needed to induce cardiac effects (M2 receptors). As a result, the measured plasma scopolamine concentration does not necessarily correlate with the extent of pharmacodynamic effects of the drug. Scopolamine pharmacodynamics only quantitatively differs from that of atropine. Whereas atropine has almost no detectable effects on CNS in clinically applicable doses, scopolamine exerts prominent CNS effects at low therapeutic doses. This difference may be explained by a better penetration of scopolamine through the blood brain barrier. Adverse effects associated with the use of scopolamine can, in the majority of cases, be attributed to an extension of its pharmacodynamic effects, and result from excessive anticholinergic activity (Renner et al., 2005; Nachum et al., 2006).

    The commonest side effects reported for scopolamine therapy are sedation, dry mouth, blurry vision, central cholinergic syndrome, and confusion (Apfel et al., 2010). Scopolamine produces mydriasis and cycloplegia by paralyzing the sphincter muscle of the iris and the ciliary muscle of the lens. These effects on eye may last up to 7–12 days after a topical application of scopolamine. Although, systematically administered scopolamine has little effect on the intraocular pressure, patients with narrow-angle glaucoma may develop dangerous increases in the intraocular pressure following scopolamine (Renner et al., 2005). Additional side effects include reduction of gastric secretions and salivation, decreases in smooth muscle tone in the gastrointestinal tract, leading to a hypomotility, dryness of the nasopharynx, mouth, bronchi, and bronchioli. Following smooth muscle relaxation after scopolamine administration, the airway resistance in the respiratory tract is reduced. The drug exerts a similar relaxing effect on the smooth muscle tone of urethra and bladder (Renner et al., 2005).

    Clinical Efficacy

    Transdermal delivery system patches have proved to be highly effective in the management of motion sickness and PONV. This is also supported by experimental data and studies on human volunteers, showing a higher efficacy of TDS compared to placebo (Table 1; Graybiel, 1979; Graybiel et al., 1981, 1982; Dahl et al., 1984; Shojaku et al., 1993). Kotelko et al. (1989) studied patients undergoing elective cesarean delivery under epidural anesthesia with the addition of epidural morphine for postoperative analgesia. They reported a significant reduction in nausea, vomiting, and retching when comparing the TDS group vs. placebo during the study period of 2–10 h after surgery. Additionally, the TDS group required less antiemetic medication during the first 24 postoperative hours. The adverse effects experienced by the patients in both groups were dizziness (8%), blurred vision (4% in TDS group vs. 2% placebo group) and disorientation (1% TDS group vs. none in the placebo group). As it was shown, side effects were minimal in both groups (Kotelko et al., 1989). Harnett et al. (2007) carried out a similar study in women undergoing cesarean delivery under spinal anesthesia and induced opioid analgesia to compare the effects of TDS, placebo, and ondansetron on PONV. They administered antiemetic prophylaxis after clamping the umbilical cord instead of applying the TDS before surgery as Kotelko et al. (1989) reported. This relevant difference should be considered in order to avoid potential exposure of the fetus and consequent side effects. Their results showed that TDS was significantly superior to ondansetron or placebo as a PONV prophylactic therapy. The overall postoperative emesis rate was 59.3% in the placebo group and was reduced to 40% in the scopolamine group and 41.8% in the ondansetron group, respectively. The authors evaluated the effects of aforementioned drugs at different time periods postoperatively (0–2 h, 2–6 h, and 6–24 h), and it was concluded that the efficacy of scopolamine was higher compared to ondansetron or placebo during the postoperative 6–24 h interval. The side effects reported during the study did not lead to discontinuation of drug use in any patient. Dizziness varied significantly among the groups, but the relative incidence was not consistent across the time intervals. Dry mouth was somewhat more common in the scopolamine group in the 6–24 h interval (9% in placebo group, 4% in ondansetron group, 19% in scopolamine group). Similarly, blurry vision was more common in the scopolamine group than placebo at 6–24 h (6% vs. 0%). Lethargy occurred in < 10% of subjects during all time intervals, and its frequency did not differ among the groups. The differences in drug effects at different time periods may be related to the pharmacokinetic and pharmacodynamic properties of the drug (Harnett et al., 2007).

    TABLE 1

    TABLE 1. Characteristics and overview of studies using transdermal scopolamine to prevent postoperative nausea and vomiting or post discharge nausea and vomiting.

    Einarsson et al. (2008) concluded that the TDS significantly reduces the incidence and severity of nausea and vomiting in the first 24 h after gynecologic laparoscopic surgery. They found a significantly higher rate of visual disturbances compared with the placebo group (45.8% vs. 8.3%). Symptoms of dry mouth were also slightly more common in the scopolamine group, but generally did not seem to be bothersome to study participants (87.5% vs. 79.2%; Einarsson et al., 2008). Jones et al. (2006) compared the efficacy of active TDS plus ondansetron with a placebo patch plus ondansetron in high-risk patients scheduled to receive a short duration general anesthesia for no longer than an hour. They found that patients receiving a combination of TDS and ondansetron reported fewer incidences (39%) of PONV compared to those who received ondansetron alone (75%). The most frequently reported side effect was headache, which has been attributed to ondansetron (Jones et al., 2006). White et al. (2007) compared a combination of TDS with droperidol vs. TDS with ondansetron in patient undergoing major laparoscopic surgeries, the study showed that both combinations were equally effective in preventing nausea and vomiting during the first 72 h of the post-operative period with a complete response of 41 and 51%, respectively (White et al., 2007).

    Recently, a study by Sah et al. (2009) showed the efficacy of TDS plus ondansetron vs. placebo patch plus ondansetron on the incidence of PONV in 126 patients undergoing plastic surgery. A statistically significant reduction in postoperative nausea between 8 and 24 h in patients who received TDS was observed. During the first 4 h, no significant difference between the two groups was revealed, which may be attributed to ondansetron administration in both groups. The most common side effect was dry mouth in 70% of patients in the transdermal group compared with 63% in the placebo group. Visual disturbance was found in 15% of the TD group compared to 5% of patients in the placebo group. Sedation was common and notable in 40% of TD group vs. 33% of the placebo group, probably related to postoperative opioid use (Sah et al., 2009). Gan et al. (2009) confirmed the previous findings; they expanded the time of observed effectiveness of TDS with data collected from 0–48 h postoperatively and included the largest sample size to date. The study examined active TDS plus ondansetron compared with placebo patch plus ondansetron as a prophylactic treatment for PONV in 620 female patients undergoing outpatient laparoscopic or breast augmentation surgery. This study found a significant reduction in PONV incidence 24 h after surgery in the group receiving TDS plus ondansetron compared to the reference group that received placebo patch plus ondansetron. Despite the fact that TDS has a slow onset of action, this study showed that the clinical benefits are apparent when TDS is administered in combination with ondansetron 2 h before induction of anesthesia. In addition, this trial observed that the overall incidence of adverse events was less frequent in the group receiving TDS in combination with ondansetron compared with the group receiving ondansetron alone (36.7% vs. 49%; Gan et al., 2009). The combined use of TDS and dexamethasone by Lee et al. (2010a) showed that patients undergoing major orthopedic surgery using patient-controlled analgesia (PCA) was more effective in preventing PONV compared with dexamethasone alone or dexamethasone plus ramosetron (47.5% vs. 82.5% and 50.0%, respectively; Lee et al., 2010a). Limitations of this study include the lack of a control group without prophylaxis, the 24 h limits of patient evaluation after surgery, inability to evaluate the drug’s effects on the urinary function because of the presence of an indwelling urinary catheter (Lee et al., 2010a). Lee et al. (2010a) designed a similar randomized controlled trial that evaluated the efficacy of preventing nausea using TDS with ondansetron vs. ondansetron alone after uterine artery embolization (UAE). The overall incidence of nausea after UAE was low; there was a lower level of nausea in patients treated with TDS compared to the group that did not receive ondansetron during the first 24 h after embolization. Adverse events were more common with the TDS group, with two patients experiencing episodes of profound disorientation and 71% reporting substantial dry mouth. These results suggest that although the TDS provides moderate reduction of nausea, its use is associated with infrequent but notable episodes of patient disorientation.Therefore, the decision whether to use or not a TDS should be based on careful consideration of the potential benefits vs. the possibility of unwanted side effects for a given practice setting (Lee et al., 2010b). Green et al. (2012) compared aprepitant alone vs. aprepitant with scopolamine in patients undergoing elective surgical procedures and with two or more Apfel four-point risk factors. The study showed no difference in complete response (63% vs. 57%, P = 0.57) between both groups In addition, there was no difference between the numbers of patients who did not report any PONV those who used a rescue medication (Green et al., 2012). Clinical trials with TDS have consistently demonstrated its safety and efficacy as an antiemetic in many medical situations that frequently result in severe nausea and vomiting. In a meta-analysis study, Apfel et al. (2010) revealed a reduced risk of severe nausea and vomiting in patients receiving TDS compared to patients receiving placebo. TDS was shown to reduce the risk of postoperative nausea (relative risk, RR = 0.77; 95% CI, 0.61-0.98; P = 0.03) The most prevalent side effect registered at 24–48 h after surgery was the occurrence of visual disturbances (RR = 3.35; 95% CI, 1.78–6.32) (Apfel et al., 2010).

    Safety and Toxicity

    Studies have consistently shown that the TDS is safe and well tolerated initially in patients treated for motion sickness. Later studies showed its efficacy for prophylaxis of PONV in patients undergoing various surgical procedures, including abdominal, and orthopedic. The most common side effects described throughout the different studies were dry mouth (~29%), dizziness (less than 8%), blurred vision (less than 4%), and disorientation (less than 1%; Package Insert, 2006). TDS is not recommended for administration in children and should be used with special caution in patients with pyloric obstruction, intestinal obstruction, impaired liver, and kidney function, obstructive urinary dysfunction, and glaucoma. The patch is contraindicated in patients hypersensitive to scopolamine and other belladonna alkaloids, as well as plaster allergies (Renner et al., 2005; Package Insert, 2006). In pregnant women, scopolamine should be administered only when potential benefits will overweight the risks to the fetus. Currently, there are not enough data to prove Scopolamine’s safety in pregnant or lactating mothers (Ayromlooi et al., 1980; Evens and Leopold, 1980; Briggs et al., 1994), although the drug is considered compatible with nursing and is not considered teratogenic. Scopolamine toxicity has been described in a newborn with symptoms such as tachycardia, fever, and lethargy (Renner et al., 2005).

    Discussion

    Despite the recognition of PONV as a contributing factor to postoperative morbidity, it still remains an actual medical problem necessitating a search for newer therapies. Current PONV risk stratification tools are helpful in providing a semi-quantitative risk assessment of PONV. Nevertheless, newer approaches and screening methods are to be developed to better reflect the patients’ and clinicians’ perception of PONV, provide a reliable means of high-risk patient selection, and reduce the overall impact of this complication on perioperative outcome. PONV pharmacotherapy and prophylaxis are based on monotherapy using a single antiemetic or combinations of several drugs. Multiple clinical trials have proven the safety and clinical efficacy of the TDS in treatment of PONV in various patient groups when used as a single drug or in combination with other drugs. TDS may be an effective method of PONV prophylaxis when applied within 2 h prior to surgery and anesthesia (Kotelko et al., 1989; Reinhart et al., 1994; Jones et al., 2006; White et al., 2007; Gan et al., 2009; Sah et al., 2009; Lee et al., 2010a, b; Green et al., 2012). This can be explained by the fast release and absorption of the loading dose in the inner layer of the patch.

    The most recent consensus guidelines for the management of PONV address the issue of providing antiemetic therapy in those patients in whom prophylaxis has failed. They recommend that an antiemetic from a different pharmacologic class than the drug(s) administered for prophylaxis be given (Gan et al., 2014). They cite that the 5-HT3 antagonist class as being the only class that have been extensively studied for the treatment of existing PONV, and that this class should be administered prefererentially if not already given for prophylaxis. The guidelines also list alternative treatments to treat established PONV including dexamethasone, droperidol, or promethazine, and low dose propofol (Gan et al., 2014). If TDS is selected as a first-line agent for PONV prophylaxis medication, then this would leave more of the other drug classes available to treat established PONV if prophylaxis happens to fail. Due to the longer duration and pharmacokinetic profile, TDS may also be beneficial for prevention of PDNV, although further studies need to be performed to study this effect.

    In conclusion, an effective management of PONV mandates understanding the pathophysiological mechanisms of PONV development and pharmacologic profiles of the applied medications, as well as their interaction with anesthetics, and other drugs used during the perioperative period. Effective reduction of the frequency and severity of PONV in various patient groups can be achieved with judicious use mono- or combination pharmacotherapy or non-pharmacological methods. Current scientific evidence indicates that TDS may be effectively used for prophylaxis and therapy of PONV.

    Sergio D. Bergese has a consulting agreement with Baxter Healthcare Corporation, active since 2010. TDS is licensed by Baxter Healthcare Corporation. Joseph V. Pergolizzi is a consult for Baxter Healthcare Corporation, Eisai Inc., Hospira and GlaxosmithKline.

    Acknowledgments

    The authors would like to thank, Ala-Eddin Sagar, for his valuable contribution to the research and preparations of this manuscript and Keri Hudec for her editorial assistance.

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