Continuing Education Activity

Dextromethorphan received FDA approval in 1958 for its use as a cough suppressant. It is one of the most common compounds found in most over-the-counter antitussives for the past 50 years. In 2010, the FDA approved the use of dextromethorphan for pseudobulbar affect in combination with quinidine. This activity will highlight the mechanism of action, adverse event profile, approved and off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions of dextromethorphan, pertinent for members of the interprofessional team using dextromethorphan for any of its intended indications.

Objectives:

• Identify the mechanism of action of dextromethorphan.
• Outline the approved and other indications for therapy with dextromethorphan.
• Review the adverse event profile for dextromethorphan.
• Explain the importance of improving care coordination among the interprofessional team to enhance care delivery for patients when using dextromethorphan.

Indications

Dextromethorphan (DM) received FDA approval in 1958 for its use as a cough suppressant. It has been one of the most common compounds found in most over-the-counter antitussives for the past 50 years.[1]

In 2010, the FDA approved the use of DM for pseudobulbar affect (PBA) combined with quinidine. PBA is a neurologic dysfunction of emotional expression characterized by outbursts of crying or laughing inappropriately and disproportionately to the mood. The pathology of PBA is still incompletely understood. Still, the leading hypothesis suggests that it is due to a loss of descending cortical control of brainstem motor nuclei and the cerebellum. This loss of control disrupts inhibitory mechanisms for motor control of emotional expression.[2][3]

Many other potential therapeutic uses for DM are currently under investigation in clinical studies. Most of these use the property that DM has as a neuroprotective agent. These indications include[4]:

• Depression: DM has a fast-acting antidepressant activity for its similarity to ketamine.
• Stroke: Studies have shown that DM has a role in the improvement of some neurological and psychiatric complications, however, not the overall functional outcomes.
• Traumatic Brain Injury: Although the studies have shown limited effects, there are proposed mechanisms that confer the benefits of DM in TBI, including its activity at NMDA and sigma-1 receptors.
• Seizure: Some clinical studies have shown that DM has efficacy in refractory seizures.
• Pain: There are studies on the analgesic effects of DM for pain conditions such as cancer-related, post-operative, neuropathic, and gastrointestinal pain.
• Methotrexate Neurotoxicity: DM showed a complete resolution in neurologic deficits associated with MTX toxicity in 5 cases.
• Parkinson disease: DM meliorated primary Parkinson disease in 2 studies.
• Autism: Contradicting data regarding DM's role in behavioral improvement.

Mechanism of Action

Dextromethorphan has multi-faceted pharmacodynamic and pharmacokinetic properties. The drug is a lipophilic molecule with an ionizable amine at one end. It is structurally related to alkaloid opioids such as morphine but does not interact with the mu receptor. It derives from levorphanol, first designed as a morphine alternative. The main mechanism of action for its use in the cough suppressant is not completely understood. One proposed mechanism is that DM works on the nucleus tractus solitarius, the estimated site where the pulmonary vagal afferent fibers synapse in the central nervous system. This site in the brainstem functions as a gate for the cough reflex. DM is known to have many interactions with several different receptor sites.[4][5]

DM is a synthetic analog of codeine and undergoes rapid metabolism upon initial absorption. Its metabolism is via cytochrome P450 2D6 (CYP2D6) into major O-demethylated metabolite, dextrorphan (DX). DX is further glucuronidated by uridine diphosphate-glucuronosyltransferase to form dextrorphan-o-glucuronide, the most prevalent form of DX present in the plasma (98%). Dextrorphan-o-glucuronide is permanently charged and has less permeability to the blood-brain barrier. DM also gets metabolized into 3-methoxymorphinan via cytochrome P450 3A4.[1][4]

DM has low oral bioavailability due to its extensive first-pass metabolism; however, this is also dependent on different metabolizers. People may fall under different metabolic groups: ultrarapid, extensive, intermediate, and poor metabolizers. Most of the population falls under the extensive metabolizer. A single oral dose of 30mg of DM showed a median half-life of 2.4 hours with an oral bioavailability of 1 to 2%. Approximately 9% of the population are poor metabolizers. After a single dose orally, the median half-life of DM is 19.1 hours, with an oral bioavailability of 80%. Poor metabolizers have approximately four-fold higher plasma levels of DM.[1][4]

Although structurally similar, DM does not have a direct action on the opioid receptors that produce classic CNS effects of opioid agonists. DM is known for its main site of action at N-methyl-D-aspartate (NMDA) receptors as a non-competitive antagonist. However, studies have found many sites of action with which DM and DX interact.[1][4][5]

Other sites of action include:

• Sigma-1 receptors agonist
• Nicotinic receptors (a3b4, a4b2, a7) antagonists
• Serotonin transporters inhibitor
• Norepinephrine transporters inhibitor
• Voltage-gated calcium channels inhibitor

Administration

Dosing and administration of dextromethorphan are mostly via the oral route. There are many formulations for administration:

• Combination liquid cough syrups; the common OTC formulation contains 15 mg/5mL of DM; recommended adult dosing is 2 tsp (10ml) every 4 hours.
• Sustained-release cough syrup suspensions; another OTC product contains 30 mg/5mL
• Liquid filled capsules containing 15 or 30 mg of DM
• Oral strips containing 7.5 or 15mg of DM
• Lozenges containing 5, 7.5, 10 mg of DM

The recommended dosing for DM is 0.5 mg/kg up to 30 mg, administered three or four times a day.

Some animal studies have suggested that to reach the potential neuroprotective effects requires the ingestion of doses higher than typically used for antitussive effects (60 to 120 mg/d).[6]

For PBA, the FDA has approved the use of DM in combination with quinidine, a CYP2D6 inhibitor. The approved dose is 20 DM and 10mg quinidine in capsule form.[2]

Specific Patients Population 

• Patient with Hepatic Impairment: There is no dose adjustment guidance in the manufacturer label for patients with hepatic impairment. 
• Patient with Renal Impairment: There is no dose adjustment guidance in the manufacturer label for patients with renal impairment. 
• Pregnant Women: It is considered as pregnancy category C medicine. It is mainly metabolized in the liver via CYP2D6 and CYP3A enzymes. Activities of these enzymes increased in pregnant women.[7][8] Standard doses of dextromethorphan are generally considered acceptable during pregnancy. However, It is recommended to avoid alcohol-containing dextromethorphan products during pregnancy.
• Breastfeeding Women: There is a very low amount of dextromethorphan and its active metabolite excreted in breastmilk. It is not expected to have any adverse effect on the infant in this amount. However, it is recommended to avoid Dextromethorphan products that contain high alcohol levels.[9]
• Pediatric Patients: The safety and efficacy of dextromethorphan on infants and very young children (less than 4 years) are not established by any systemic clinical trials in pediatric patients. 
• Geriatric Patients: There is no specific dose adjustment needed for geriatric patients.

Adverse Effects

Adverse effects from cough suppressants are rare. The most common are nausea and gastrointestinal discomfort, while drowsiness and dizziness can also occur.

One study showed at high doses (greater than 4 mg/kg), up to 64% of patients felt euphoria, and some experienced various CNS effects such as visual hallucinations and persecutory delusions. In addition, these episodes were associated with agitation, leading to patient management difficulties.

The most common side effects in this study were the sensation of a drunk feeling or a "high" (20%), nausea and vomiting (17%), nystagmus (15%), and dizziness (15%). Most side effects resolved within a day after the final dose, and no cardio-respiratory compromises were noted. Serum levels of DM exceeding 400 ng/ml presented in 87.5% of patients with these side effects. More than 60% of the patients who experienced side effects with DM had serum levels exceeding 120ng/ml and brain levels of 700 ng/g.[10]

Contraindications

Dextromethorphan is contraindicated for patients with known or established hypersensitivity and those with an idiosyncratic reaction upon administration of the drug.

It is not recommended to coadminister dextromethorphan with monoamine oxidase inhibitor (MAOI) or for two weeks after stopping the MAOI drugs.[11]

Since DM comes in combination with different medicines, consider contraindications of each ingredient for safe prescribing of combination products.

Monitoring

Dextromethorphan is well tolerated and has a wide therapeutic window, making it an amenable drug for clinical use.

Toxicity

One concern regarding dextromethorphan toxicity is its OTC misuse that has been increasing since the 2000s. DM misuse is known as "going pharming," "robotripping," and "dexing." In 2006, three different OTC product formulations accounted for 66% of reported instances of DM misuse in the USA. One life-threatening toxicity associated with DM abuse is serotonin syndrome. Due to its action on serotonin reuptake inhibition, if patients are already on common SSRI or MAOI antidepressants, DM toxicity potentiates excess serotonin in the body, potentially leading to serotonin syndrome. These include agitation, confusion, dilated pupils, headache, tachycardia, hypotension, high fevers, seizures, irregular heartbeat, and can lead to unconsciousness.[12]

Enhancing Healthcare Team Outcomes

Dextromethorphan (DM) misuse and overdose have increased significantly since its introduction to its over-the-counter market. Diagnosis and management of DM overdose require an interprofessional team of healthcare professionals, including clinicians, mid-level practitioners, nurses, pharmacists, and any witnesses or family members. Careful documentation of past medical history and current medications is crucial in diagnosing one of its major overdose complications. Treatment for serotonin syndrome includes hydration, withdrawing the drugs, managing body temperature, and seizures. Without proper management, serotonin syndrome and DM overdose may be fatal.[13]

The paramedics have a crucial role in identifying any witnesses or empty pill bottles at the scene. The triage nurse has an essential role in suspecting a possible drug overdose and must guide patient admission accordingly. A careful history is necessary to initially distinguish the time of onset as well as later on when more serious effects may occur or when the condition of the patient deteriorates. The emergency department physician is responsible for ordering appropriate lab work when suspecting a drug overdose, including drug levels in the blood and/or urine. When appropriate, consultation must occur with pharmacists, toxicologists, radiologists, and hospitalists.

There are two grades of recommendation. Grade D includes patients with suicidal ideation, intentional abuse, or malicious intent; all should obtain a referral to the nearest emergency department. Grade C includes patients who show more than mild effects of DM overdose or after acute drug ingestion. These patients should get referred to the nearest emergency room. Patients who have ingested 5 to 7.5 mg/kg should follow poison control center-initiated treatment and follow up every 2 hours up to 4 hours. If more than mild symptoms continue or develop, they should be immediately sent to the emergency room. Any amount of drug ingested more than 7.5mg/kg should be sent to the emergency room right away.[14]