4P: Overview of Dextromethorphan

Course Opening Up June 16, 2023.

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Learning Objective:

• Recognize the potential dangers and interactions of the common over the counter drug dextromethorphan.

I have seen three cases of serotonin syndrome.  Pharmacists need to be cognizant of the potential interaction between “good old Dextromethorphan” and antidepressants that can lead to increased serotonin levels.

1. Back in 2007 one of my patients came into the pharmacy with her husband.  She was a thin and frail woman of about 40 years of age and weighed around 100 pounds, presenting with clonic jerking of her arms.  I asked her husband what was going on, and he said, “she had a drug interaction between her Prozac-40 and Robitussin DM cough syrup.” 
2. We had a patient at the primary care practice that I staffed that was “chugging Nyquil” for a bad cough.  She ended being flown via helicopter to a Pittsburgh hospital due to excess dextromethorphan ingestion, while taking Citalopram 40mg once daily.
3. On Monday when I was working on the bench a patient called.  She was taking Fluoxetine 40mg, and Quetiapine 100mg twice daily.  Her doctor just added Trazodone 50mg at bedtime to help her sleep.  The patient said she developed a tremor on both hands. I told the patient to call the prescriber and to consider stopping the trazodone due to possible serotonin syndrome.  The prescriber called and asked me if I thought the trazodone was really the culprit since it was a low dose of 50mg.  I told the nurse practitioner that there is a lot of patient variability with this condition and since the tremors presented since starting trazodone, it would be prudent to start there.  The NP thanked me for my advice and took my recommendation.

Table of Contents

Dextromethorphan (DXM) HISTORY: 

The FDA approved DXM in 1958 and during the 1960s and 1970s, dextromethorphan became available in an over-the-counter tablet form by the brand name Romilar®. In 1973, Romilar® was taken off the shelves because of frequent misuse and was replaced by cough syrup to cut down on abuse. Manufacturers began introducing refined DXM products (Robitussin-DM®, Vicks-44®) that were designed to limit recreational use by creating an unpleasant taste if consumed in large quantities¹.  It wasn’t long ago that we remember that the drug companies started marketing a higher concentration, and more pleasant tasting preparation (Delsym®). Keep in mind when the recommended dose is taken, DXM has few adverse side effects, and has a long history of safety and efficacy.

 

PHARMACOLOGY:

Dextromethorphan is the d-isomer of the codeine analog of levorphanol¹. Older “seasoned” pharmacists remember dispensing levorphanol under the brand name of Levo-Dromoran a Schedule-2 narcotic made by Roche and FDA approved in 1953.  It is still available as a generic for almost $40.00 per PILL²! Dextromethorphan is a codeine like drug that binds to and acts as antagonist to the NMDA glutamatergic receptor, it is an agonist to the opioid sigma 1 and sigma 2 receptors, it is also an alpha3/beta4 nicotinic receptor antagonist and targets the serotonin reuptake pump.  The net effect is DM decreases the sensitivity of cough receptors and interrupts cough impulse transmission by depressing the medullary cough center in the brain³.

• Rapid GI absorption.
• Half-life= 1.5-2.2 hours. Substrate of CYP450: 3A4, 2D6, so watch for drug interactions³.
• First-pass through the hepatic portal vein results in some of the drug being metabolized into an active metabolite of dextromethorphan, dextrorphan, the 3-hydroxy derivative of dextromethorphan.
• Easily crosses the blood brain barrier.

 

Pediatric dosing:

• Children less than 4 years: Not for OTC use⁴
• Children 4-6 years (syrup): Oral: 2.5-7.5 mg every 4-8 hours; extended release (Delsym) is 15 mg twice daily (maximum: 30 mg/24 hours)³
• Children 6-12 years: 5-10 mg every 4 hours or 15 mg every 6-8 hours; extended release is 30 mg twice daily (maximum: 60 mg/24 hours). Over age 12 use the adult dose³.

 

 

WARNINGS:

Serotonin syndrome occurs when drugs that increase serotonin levels are combined with other drugs that increase serotonin levels.  Dextromethorphan can precipitate a serotonin syndrome event.  Symptoms of agitation, confusion, hallucinations, hyper-reflexia, muscle twitch/jerk, shivering, and tachycardia.  Serotonin syndrome may occur with drugs such as³:

• SSRI/ SNRI (antidepressants like fluoxetine, paroxetine, venlafaxine, and duloxetine etc.)
• Monoamine oxidase inhibitors MAOI (for Parkinson’s and depression)
• Tramadol especially at high doses
• Trazodone (over 150mg)
• Linezolid (Zyvox) which has some MAO inhibition effect.

 

Novel Use for Dextromethorphan, that illustrates the mental effects of this drug:

Nuedexta® Rx-

(dextromethorphan/quinidine) is a new drug designed to treat PseudoBulbar Affect (PBA) which is caused by neurologic conditions such as Alzheimer’s disease, stroke, traumatic brain injury (TBI), Parkinson’s disease, multiple sclerosis (MS), or Lou Gehrig’s disease (ALS).
Symptoms outbursts of crying or laughing that are often sudden and exaggerated or do not match what the person is feeling inside. This drug contains 20mg DM and 10mg quinidine. It works by using quinidine to block the metabolism of DM for a prolonged effect in treatment of PBA⁵.

 

DXM ABUSE:

• Most abused: Coricidin® HBP (DM-30mg + Chlorpheneramine-4mg), often referred to as “CC” or “triple C” or “Skittles”.  Robitussin products can be used, called “Robo-tripping” or “Robo-shakes”.  May lead to elevated body temperature and death.
• Symptoms following ingestion of high doses (five to ten times the normal therapeutic dose) include euphoria, an altered sense of time, paranoia, and disorientation. In addition, tactile, visual, and auditory hallucinations may occur¹.
• The effects seen with dextromethorphan abuse are like those seen after phencyclidine (PCP) use, another agent which blocks NMDA receptors.  DXM is sometimes referred to as “Poor man’s PCP”.’

EFFECTS of EXCESSIVE DXM INTAKE¹:

• Increased perceptual awareness.
• Altered time perception.
• Feelings of “floating” or dissociation of the body.
• Visual disturbances
• Tactile, auditory, visual hallucinations
• Paranoia
• Disorientation and lack of coordination
• Slurred speech
• Impaired judgment and mental performance

Below is a chart I prepared to illustrate the doses needed to cause all the levels of DXM intoxication.  As you can see, just one bottle of Delsym® (89ml) can cause an abuser to experience dissociative sedation.  I am much more concerned about the Delsym® and the Coricidin® products, because as we all know excess guaifenesin causes nausea and most likely vomiting.

Table 1^1,3:

Plateau	Dose (mg)	Behavior effects	Robitussin DM®	Delsym®	Coricidin HPB®
1st	100-200	Mild stimulation	50-100mL	17-34mL	3-7 tabs
2nd	200-400	Euphoria, hallucinations	100-200mL	34-68mL	7-14 tabs
3rd	300-600	Distorted visual perception, Loss of coordination	150-300mL	50-100mL	10-20 tabs
4th	500-1500	Dissociative sedation	250-750mL	83-250mL	17-50 tabs

 

The Following state prohibit sales of Dextromethorphan to minors:

• Maryland effective October 2007
• California effective January 1, 2012.
• New York effective March 26, 2014.
• Rhode Island effective 2014
• Virginia effective January 1, 2015.
• Washington effective July 1, 2015. 
• Arizona effective July 24, 2014.
• Louisiana effective August 1, 2014
• Kentucky effective March 2015
• Tennessee effective January 1,2016
• New Jersey effective February ,2016
• Alaska effective Mary 2016
• Delaware effective June 2016
• Florida effective January 2017
• Nevada effective June 2017
• Oregon effective January 2018
• Colorado effective August 2018
• Wisconsin effective January 2019
• Texas effective September 2019
• Michigan effective July 2020
• Ohio effective September 2021

Have a great day on the bench!!

Questions:

1 When dextromethorphan is taken with drugs like antidepressants it can lead to an increase of serotonin in the brain. This is called:

A: Drug abuse

B: Drug induced euphoria

C: Serotonin syndrome

D: synergistic medication use

            ANSWER = C

2 What are the dangers if a patient accidentally ingests 50mL of Delsym® instead of 5mL?

                                    A: Euphoria, hallucinations, and mild stimulation

                                    B: Tachycardia and hypertension

                                    C: Bradycardia and hypotension

                                    D: None of the above, Delsym® is an exceptionally safe drug

            ANSWER = A

References:

1. Rosenbaum MD. Dextromethorphan abuse and poisoning: Clinical features and diagnosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com (Accessed on May 26, 2023.)
2. In: Lexi-Drugs. Lexi-Comp, Inc. Updated May 17, 2023. Accessed May 26, 2023
3. In: Lexi-Drugs. Lexi-Comp, Inc. Updated May 24, 2023. Accessed May 26, 2023
4. Should you give kids medicine for coughs and colds? FDA. January 5, 2023. Accessed May 26, 2023
5. Nuedexta [package insert]. Aliso Viejo, CA: Avanir Pharmaceuticals, Inc.; 2010.

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