Dextromethorphan

Article Author:
SaeRam Oh
Article Author (Archived):
Suneil Agrawal
Article Editor:
Alan Taylor
Updated:
10/2/2019 9:36:10 AM
PubMed Link:
Dextromethorphan

Indications

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

In 2010, the FDA approved the use of DM for pseudobulbar affect (PBA) in combination 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, but 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]

There are many other potential therapeutic uses for DM that 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 complete resolution in neurologic deficits associated with MTX toxicity in 5 cases
  • Parkinson's Disease: DM meliorated primary Parkinson's 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 opioid such as morphine but does not interact with the mu receptor. It was derived from levorphanol, first designed to be used 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. This is the most major 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. The median half-life of DM after a single dose orally is 19.1 hours with an oral bioavailability of 80%. Poor metabolizers have approximately four-fold higher plasma level 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 that 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

Dextromethorphan is taken orally, mostly. There are many formulations for administration:

  • Combination liquid cough syrups; the common OTC formulation contains 15 mg/tsp 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 that doses higher than typically used for antitussive effects must be ingested (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 20/10mg.[2]

Adverse Effects

Adverse effects from cough suppressant are rare. Most commonly nausea and gastrointestinal discomfort with drowsiness and dizziness can occur. One study showed at high doses (greater than 4mg/kg), up to 64% of patients felt euphoria and some experienced various CNS effects such as visual hallucinations and persecutory delusions. These episodes were associated with agitation, leading to patient management difficulties. The most frequent side effects in this study were a sensation of drunken 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. The DM serum level greater than 400ng/ml resulted 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 700ng/g.[7]

Contraindications

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

Monitoring

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

Toxicity

One concern regards to 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 and produces a group of symptoms called serotonin syndrome. These include agitation, confusion, dilated pupils, headache, tachycardia, hypotension, high fevers, seizures, irregular heartbeat and can lead to unconsciousness.[8]

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 professions including any witness or family members. Careful documentation of past medical history and current medications are 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.

The paramedics have a crucial role in identifying any witnesses or empty pill bottles at the scene. The triage nurse has an essential part in suspecting a possible drug overdose and must guide patient admission accordingly. A careful history must be taken to distinguish time of onset initially and 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 blood and/or urine. Consultation must occur with pharmacists, toxicologists, radiologists, and hospitalists when appropriate. 

There are two grades of recommendation. Grade D include patients with suicidal ideation, intentional abuse, malicious intent all should obtain a referral to the nearest emergency department. Grade C include 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 sent to the emergency room immediately. Any amount of drug ingested more than 7.5mg/kg should be sent to the emergency room right away.[9]


References

[1] Taylor CP,Traynelis SF,Siffert J,Pope LE,Matsumoto RR, Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacology     [PubMed PMID: 27139517]
[2] Pioro EP, Review of Dextromethorphan 20 mg/Quinidine 10 mg (NUEDEXTA(®)) for Pseudobulbar Affect. Neurology and therapy. 2014 Jun;     [PubMed PMID: 26000221]
[3] Patatanian E,Casselman J, Dextromethorphan/quinidine for the treatment of pseudobulbar affect. The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists. 2014 Apr;     [PubMed PMID: 24704895]
[4] Nguyen L,Thomas KL,Lucke-Wold BP,Cavendish JZ,Crowe MS,Matsumoto RR, Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders. Pharmacology     [PubMed PMID: 26826604]
[5] Corado CR,McKemie DS,Knych HK, Pharmacokinetics of dextromethorphan and its metabolites in horses following a single oral administration. Drug testing and analysis. 2017 Jun;     [PubMed PMID: 27580591]
[6] Werling LL,Lauterbach EC,Calef U, Dextromethorphan as a potential neuroprotective agent with unique mechanisms of action. The neurologist. 2007 Sep;     [PubMed PMID: 17848867]
[7] Lauterbach EC, An extension of hypotheses regarding rapid-acting, treatment-refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan. Medical hypotheses. 2012 Jun;     [PubMed PMID: 22401777]
[8] Ganetsky M,Babu KM,Boyer EW, Serotonin syndrome in dextromethorphan ingestion responsive to propofol therapy. Pediatric emergency care. 2007 Nov;     [PubMed PMID: 18007217]
[9] Chyka PA,Erdman AR,Manoguerra AS,Christianson G,Booze LL,Nelson LS,Woolf AD,Cobaugh DJ,Caravati EM,Scharman EJ,Troutman WG, Dextromethorphan poisoning: an evidence-based consensus guideline for out-of-hospital management. Clinical toxicology (Philadelphia, Pa.). 2007 Sep;     [PubMed PMID: 17849242]