Accurate Education – Dextromethorphan (DXM)

Dextromethorphan (DM or DXM)

 

Dextromethorphan (DXM) is a commonly used cough suppressant marketed as Delsym and included as the “DM” component of Robitussin DM and other OTC cough medications. Dextromethorphan has been found to be a potentially  effective agent in the treatment of chronic pain, especially neuropathic pain, opioid tolerance and hyperalgesia, central sensitization and depression. There is growing research investigating the clinical usefulness of this medication.

 

Dextromethorphan is classified as an NMDA receptor antagonist, although its pharmacological profile is complex and it interact with numerous receptors including weak interactions with opioid and serotonin receptors.

 

 

It is recommended to first read the following sections to become familiarized with some of the terms and concepts related here:

 

Education – Pain

Neuropathic Pain

Neurobiology of Pain

Neurobiology of Opioids

Central Sensitization

Opioid Induced Hyperalgesia

 

 

Definitions and Terms Related to Pain

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22 Nerves 5-1-16

“It is easier to find men who will volunteer to die, than to find those who are willing to endure pain with patience.”
– Julius Caesar

Dextromethorphan (DXM)

 

Dextromethorphan (DXM), patented in 1954 as a cough suppressant, is a common ingredient in more than 125 cough and cold remedies, including Delsym, Robitussin DM and many others. Structurally, DXM is structurally related to the opioid, levorphanol, although it is not itself considered an opioid. As a cough suppressant, it acts by elevating the cough threshold in the cough center located in the medulla oblongata in the brainstem by mechanisms unrelated to opioid cough suppression and it is not blocked by naloxone, an opioid antagonist.

 

Dextromethorphan also functions as an NMDA antagonist that make it potentially useful in reducing pain, especially neuropathic pain, as well as preventing nerve damage, reducing existing opioid tolerance and hyperalgesia. DXM may also protect against the neurotoxic effects of methotrexate chemotherapy in rheumatoid arthritis and cancer patients.

 

There is growing research that suggests supplementing with dextromethorphan in the treatment of chronic pain may reduce reliance on opioids and suppress the development of opioid tolerance. Some conflicting research results led researcers to suggest that NMDA antagonists could be more effective in the treatment of conditions with ongoing damage, such as diabetic neuropathy, but not in the presence of “fixed” painful lesions, such as in postherpetic neuralgia (shingles pain).

 

While research remains conflicting and still falls short of confirming definitive benefits and doses for supplementing with DXM, there are evidence-based arguments to consider the trial use of dextromethorphan in the management of chronic pain.

 

Dextromethorphan in the Treatment of Pain

As a potential opioid-sparing agent for pain, the use of DXM has been shown to be efficient and well tolerated. It is noteworthy that NMDA receptor antagonists, including DXM, are not in themselves anti-nociceptive, but rather they inhibit central sensitization and, thus, the perception of pain. The  use of NMDA antagonists, while blunting the development of a central sensitization of a nociceptive stimulus, still requires the use of an analgesic for the most effective reduction of pain perception. DXM has a higher therapeutic ratio than other NMDA antagonists, for example, ketamine, endowing it with a high safety profile even in prolonged administrations.

 

Acute Pain

The majority of the studies on the role of DXM in reducing acute postoperative pain or in reducing the consumption of analgesics compared one or two doses of oral DXM premedication with placebo in patients who underwent surgery with general anesthesia. The pioneering study of Kawamata et al. showed that a single DXM premedication of 30 or 45 mg (a dose used as a cough suppressant) administered 60 min before tonsillectomy under general anesthesia was effective in reducing post-tonsillectomy pain sensation, even upon swallowing, in adult patients.

 

In other studies of acute postoperative pain, DXM reduced pain at doses of 30-90 mg, without major side effects, and reduced the amount of analgesics in 73% of the postoperative DXM-treated patients.

 

Chronic Pain

Dextromethorphan reduces chronic pain by impacting the changes that occur in the nervous system associated with chronic pain. It also appears to reduce opioid tolerance and work synergistically with opioids so that they work more effectively for pain (See neurobiology of dextromethorphan, below.

 

In a small study of patients with long term neuropathic pain due to post-traumatic neuropathy who received 270 mg of dextromethorphan, results showed a 30% reduction in pain after a single dextromethorphan dose compared to placebo. After 1.5 hours and 2.5 to 4 hours from time of medication, there was a statistically significant difference in pain reduction.

 

Dextromethorphan and the Pain of Diabetic Peripheral Neuropathy (DPN)

Dextromethorphan has been studied in the management of DPN. In one study, high doses of DXM averaging 381 mg/day, subjects experienced a 24% reduction in their DPN pain. This and other studies failed to show benefit at DXM doses < 90mg/day.

 

In another study comparing DXM with memantine (another prescription NMDA antagonist) in treating painful DPN, DXM at an average dose of 400mg/day reduced average pain intensity by 33% and greater than 68% of DXM patients achieved “greater than moderate pain relief.” In this study memantine reduced pain intensity by an average  of 17% and greater than 68% of memantine patients achieved “greater than moderate pain relief.”

 

Dextromethorphan in Synergism with Opioids and Other Medications

Dextromethorphan and Morphine

A study was completed in 2000 in which DXM was combined with morphine (at a 1:1 dosing ratio) and given to patients with cancer pain.  In this double-blind multiple-dose trial, the interval between doses was longer in the study group, and lower doses of morphine were needed to achieve pain control. There was no difference in the number of side effects. A number of recent double-blind placebo-controlled trials that looked at the use of DXM in phantom pain also showed promising results.

 

A 2010 study combining morphine and memantine, another NMDA antagonist with the same mechanism of action as DMX, showed that the combination was more effective in the management of neuropathic pain than either medication alone. Only the combination therapy was effective in reducing the pain and disability associated with CRPS (chronic regional pain syndrome), a condition associated with significant changes in the nervous system that contribute to chronic neuropathic pain.

 

Dextromethorphan and Oxycodone

A study in mice published in 2015 looked at the combination of DXM and oxycodone in chronic pain.  It was reported that chronic oxycodone significantly reduced chronic allodynia by suppressing the activation of astrocytes and microglia in the spinal cord and reducing blood levels of proinflammatory cytokines (IL-6, IL-1β and TNF- α). Using low doses of DXM (10 mg/kg) that would not be expected to have analgesic benefit, DXM reduced the development of chronic allodynia more effectively than either oxycodone or DXM alone.

 

Furthermore, co-administration of DXM with oxycodone showed better effects than oxycodone alone in suppressing the activation of astrocytes and microglia in the dorsal horn of spinal cord which is believed to be the source of hyperalgesia and central sensitization. DXM also showed a trend to enhance the effect of oxycodone on decreasing the blood level level of proinflammatory cytokines, chemicals that trigger opioid tolerance. While this preclinical study needs further research to confirm these findings, it supports the anticipated benefit of DXM in patients taking opioids for chronic pain.

 

Dextromethorphan and Melatonin

Melatonin, a pineal neurohormone and a derivative of serotonin, regulates important biological functions including circadian rhythms, sleep, and mood. Functionally, melatonin also been shown to produces an pain-reducing effect in animal studies. Melatonin also reduces lipopolysaccharide-induced hyperalgesia (a mechanism thought to be associated with hyperalgesia, allodynia and central sensitivity) and interacts with opioid pain reduction. An animal study completed in 2015 suggests that melatonin has the potential to reduce opioid-induced hyperalgesia and tolerance, possibly by inhibiting the NMDA pathway in the spinal cord. While still limited in scope, animal studies suggest the combination of melatonin and DXM may have synergistic benefits in pain reduction.

 

Dextromethorphan and Opioid Withdrawal

Dextromethorphan Alone

Dextromethorphan can suppress opioid withdrawal symptoms. Early studies suggested that a dose of 360 mg/day dextromethorphan was effective in managing opioid withdrawal, whereas lower doses  of between 60-240mg day were less effective.  In one study, dextromethorphan 60 mg 4 times a day provided a beneficial effect in reducing the severity of opioid withdrawal symptoms, notably over days 3-6 of treatment.

 

Dextromethorphan in Combination with Memantine

DXM benefits in opioid withdrawal have been similar to results with a 60mg dose of memantine, another NMDA antagonist. A 2012 study evaluated the potential for drug interactions between dextromethorphan with memantine and concluded the two medications could be safely taken together and thus provided additive benefits.

 

Dextromethorphan in Combination with Quinidine

Quinidine is a medication that inhibits Cyp2D6, the liver enzyme that breaks down dextromethorphan, When given with dextromethorphan it allows for a prolonged and enhanced effect due to significantly higher blood levels (25-40 times higher). In a recent study using dextromethorphan in combination with quinidine (DXM-Q), it was concluded that while DXM-Q does not promise great benefit as a stand-alone for treatment, it may have a role as an additive medication in the treatment of opioid withdrawal.

 

Dextromethorphan in Combination with Clonidine

Studies have shown also that dextromethorphan may have an additive benefit when used with clonidine. In one study, a combination of dextromethorphan and clonidine resulted in milder opioid withdrawal symptoms compared to clonidine alone. In this study, a 300mg daily dose of dextromethorphan (75mg every 6 hours) resulted in a reduction of symptoms beginning on the second day.

 

Dextromethorphan Metabolism

DXM is rapidly absorbed in the gastrointestinal tract; its peak blood levels are reached at approximately 2 to 2.5 hours after oral administration. At therapeutic doses its onset of action is 15 to 30 minutes and its duration of action is 5 to 6 hours.

 

DXM is metabolized to an active metabolite, dextrorphan, in the liver by the CYP2D6 enzyme. Dextrorphan is believed to be responsible for most of the clinical benefits and side effects associated with DXM. The pharmacology of dextrorphan is similar to that of dextromethorphan (DXM). However, dextrorphan is much more potent as an NMDA receptor antagonist as well as essentially inactive as a serotonin reuptake inhibitor, but retains DXM activity as a norepinephrine reuptake inhibitor (See Neurobiology of Pain and Neurobiology of Opioids). Therefore, individuals who are compromised in their metabolism of DXM to dextrorphan due to drug interactions or genetic variants may not respond as well as expected (see below).

 

Dextromethorphan and Genetics

Dextromethorphan is metabolized via the CYP2D6 liver enzyme to an active metabolite dextrorphan which is believed to be responsible for most of the clinical benefits of taking dextromethorphan. About 15% of patients with European descent are genetically compromised in their ability to metabolize dextromethorphan and as a consequence experience less pain benefit (“intermediate” or “poor” metabolizers).

 

 Dextromethorphan and Drug Interactions

 While DXM has limited likelihood of significant drug interactions, the following precautions are advised. Because DXM may cause drowsiness, caution is advised when taking DXM with any medication with sedative properties. Dextromethorphan is known to increase serotonin levels and when taken at high doses or combined with other medications that increase serotonin levels, DXM may create risk for developing serotonin syndrome. The most common medications that increase serotonin are antidepressants (See: Serotonin Syndrome).

 

Finally, because DXM is metabolized by the CYP2D6 liver enzzymes, addition of any medication that inhibits this enzyme may increase DXM blood levels that could potentially lead to side effects and this risk is likely to be higher with high doses of DXM. Always confer with your physician and your pharmacist whenever a change is made in your medications or supplements so that an evaluation can be performed to assess for potential drug-drug interactions.

 

The Neurobiology of Dextromethorphan – How it Helps Pain 

DXM has multiple proposed mechanisms of action. DXM is an uncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, a sigma- 1 receptor agonist, and a serotonin and norepinephrine reuptake inhibitor.

See also: Neurobiology of Pain

 

NMDA receptors

The primary mechanism by which DXM offers pain benefits is through blocking NMDA receptors.(See Neurobiology of Opioids). NMDA receptors are found throughout the central nervous system, and, in contrast to the other NMDA-receptor antagonists, DM has widespread binding sites in the central nervous system.

 

Excitatory chemicals (amino acids)  play a role in the sensation of pain via the ascending pathways of the spinal cord. Following injury, the excitatory amino acids stimulate the NMDA receptors to transmit sensations of pain. Continued pain signalling leads to a state of hyperexcitabilty that results in allodynia, hyperalgesia and central sensitization. As a result of this activation of the NMDA receptors a phenomenon called “wind-up”  occurs, whereby nerve activity in the dorsal horn of the spinal cord is enhanced and prolonged which leads to both hypersensitivity to pain and reduced sensitivity to opioids. It is conceivable that DXM could reduce central sensitization and be an effective analgesic agent.

 

Norepinephrine Reuptake Inhibition (NRI) activity

Dextromethorphan’s active metabolite, dextrorphan, a much more potent NMDA antagonist than DXM,  also exhibits NRI activity which may contribute to some of the pain benefits provided by DXM through its action on the descending pain-inhibitory pathways. (See Neurobiology of Pain).

 

Sigma-1 Receptors

DM binds to NMDA receptors as a low-affinity non-competitive antagonist and binds to sigma-1 receptor as a high-affinity agonist. NMDA receptors are expressed on both microglia and astrocytes, whereas sigma receptors are expressed in microglia. It has been reported that the activation of sigma receptors reduced reactive gliosis following stroke injury in rats and that sigma-1 ligands can modulate several neurotransmitter systems through NMDA receptors. Thus the observed DM effects could be due to both its antagonistic activity on NMDA receptors and agonistic activity on the sigma receptors present in the glial cells.

 

Dextromethorphan and Methotrexate-Induced Neuropathy

Patients undergoing treatment with methotrexate for rheumatoid arthritis have reported significant improvement or resolution of neurologic complications such as memory impairment, malaise, headache, insomnia, numbness, feeling “zoned out,” sexual dysfunction and confusion with DXM. Patients on chemotherapeutic regimens with methotrexate at significantly higher than recommended doses and have developed speech problems and unilateral weakness have been successfully treated with DXM at doses of 75-150mg/day.

 

Dextromethorphan Dosing and Adverse Side Effects

DXM is very well tolerated with few side effects when taken at the same doses as recommended for cough (up to 120 mg/day). Dextromethorphan is considered to induce fewer side effects than other NMDA antagonists. The rate of side effects was minimal if a high dose is divided into smaller portions. Interestingly, 55% of the patients that reported side effects were females compared with 45% males. Subjects in the age range of 26-40 yr/old had the highest rate.

 

Research studies have evaluated a range of doses of DXM for both pain management and opioid tolerance reduction. Unfortunately, dosing standards have not been established. As such, the usual rule for medication dosing applies: Start low, Go slow. Dosing as recommended for cough, up to 120mg/day, in divided doses is a good place to start. In a study evaluating opioid tolerance and DXM, daily doses up to 480 mg/day were generally well-tolerated, limited to drowsiness and no clinically serious side effects. One unusual side effect of DXM is pruritis (itching), a consequence of histamine release – a characteristic shared by some opioids.

 

Side effects are generally dose-related: as dosing goes up, the frequency and severity of possible side effects follows:

 

Doses of < 1.5 mg/kg body weight (< 100mg for a 150 lb person):

Few if any side effects, possibly mild drowsiness or nausea

 

Doses of 1.5-2.5 mg/kg body weight (100mg to 175mg for a 150 lb person):

Increased alertness

Restlessness

Visual and auditory sensitivity

Generalized euphoria

 

Doses of 2.5-7.5 mg/kg body weight (175 mg to 525 mg for a 150 lb person):

Exaggerated auditory and visual sensativity

Imbalance and dizziness

Feeling drunk

Hallucinations

Increased energy and excitability

 

Doses of 7.5-15 mg/kg body weight (525 mg to 1050 mg for a 150 lb person):

Visual and auditory disturbances

Periods of semi-consciousness

Impaired thinking

Manic and/or panic

Partial disassociative psychosis

 

Doses of >15 mg/kg body weight (> 1050 mg for a 150 lb person):

Complete disassociative psychosis

Hallucinations and delusions

Ataxia (impaired coordination)

 

Full List of Possible Side Effects

  1. confusion
  2. giddiness
  3. slow breathing
  4. nausea
  5. vomiting
  6. agitation
  7. nervousness
  8. restlessness
  9. unsteadiness
  10. dizziness
  11. vision changes
  12. shortness of breath
  13. fast heart rate
  14. hallucinations (seeing or hearing things that do not exist)
  15. seizures
  16. coma

 

Dextromethorphan Products (OTC)

Delsym®

Delsym®  is an over-the-counter (OTC) medication recommended for cough. It is available in a 12-hour time release formulation of 30mg/5ml (or 30mg/tsp) with a maximum recommended dose of 60mg (10ml or 2 tsp) every 12 hours for cough. As noted above, higher doses may be required for pain management with caution regarding the potential for more side effects at higher doses.

 

Robitussin DM®

Robitussin DM® is another over-the-counter (OTC) medication recommended for cough. Like Delsym®, it contains DM but it also contains guaifenesin, an expectorant believed to thin cough secretions making them easier to cough up (expectorate). Guaifenesin may also have NMDA receptor antagonist activity but a trial evaluating guaifenesin in 20 patients with fibromyalgia over a 12–month observational period showed no difference in outcomes.

 

Robitussin DM® is available in many formulations containing up to 7.5mg/tsp of DM, but the multiple avaialable products contain an array of other active ingredients – always check the label for dosing instructions. It is recommend not to exceed the maximum recommended DM dose of 120mg/day (4 tsp four times/day) withoust consulting a physician. As noted above, higher doses may be required for pain management with caution regarding the potential for more side effects at higher doses.

 

Dextromethorphan Products (Rx)

Nuedexta® (Dextromethorphan-20mg/Quinidine -10mg)

Nuedexta is a prescription medication that combines dextromethorphan (20mg) with quinidine (10mg). The quinidine is included because it inhibits the liver enzymes (Cyp2D6) that metabolize (break down) dextromethorphan, thus prolonging the action of dextromethorphan. It is FDA approved for treatment of Pseudobulbar Affect disorder (PBA),  “a neurologic disorder of emotional expression characterized by frequent, sudden, involuntary outbursts of crying and/or laughing disproportionate or unrelated to the patient’s underlying mood, occurring in settings of neurologic disease or injury. PBA is commonly associated with conditions such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury, stroke, Alzheimer’s disease, and Parkinson’s disease and is thought to affect as many as 7 million people in the U.S.

 

Studies indicate that Nuedexta is generally safe and well tolerated, with no evidence of clinically relevant cardiac or respiratory effects. Nuedexta has also been evaluated  for the potential for drug-drug interaction (DDI) with memantine,  another NMDA receptor antagonist. Minimal pharmacokinetic and pharmacodynamic interactions were observed between memantine and Nuedexta, suggesting they can be administered together without dose adjustment.

 

Use of Nuedexta or dextromethophan for pain or opioid management related conditions would be considered “off-label”but studies indicate they are safe and well tolerated.

 

Dextromethorphan Withdrawal Syndrome

With prolonged use, especially with high doses, a physical withdrawal syndrome can occur. Physical withdrawal symptoms are generally mild and may include intermittent vomiting, night sweats, muscle aches, diarrhea, restlessness, insomnia, and anxiety. The DXM dependence and physical withdrawal may be secondary to serotonergic and sigma-1 opioidergic properties of the drug although DXM affinities for these receptors is considered to be minimal.

 

Dextromethorphan in the Treatment of Tolerance, Hyperalgesia and Central Sensitization

No long term studies are available that evaluate prolonged, combined use of DXM and opioids to determine the effectiveness of long term reduction of opioid tolerance, hyperalgesia and central sensitization. While study results of short term use of DXM in both acute and chronic pain support the possibility of long term benefits, the question of benefit remains unanswered.

 

Dextromethorphan as a Drug of Abuse – “Robo-Tripping”

One major factor limiting the use of DXM is its potential for abuse, as it is now recognized that at the higher doses DXM may produce a euphoric effect.

Recreational users seek the “dissociative” effects of DXM, including the hallucinations, depersonalization and feelings of being “high.” Recreational doses are typically higher than usual analgesic doses, often greater than 200 mg or higher.

 

Summary

Animal and clinical research indicate a beneficial role of DXM and other NMDA receptor antagonists as part of multi-modal analgesic therapy. In the management of chronic pain, oral DXM at doses of 30–90 mg appears to have an advantage over other NMDA antagonists in reducing the sensation of pain and sparing the requirement of conjointly administered opioids, and has proven to have no or a low rate of untoward side effects. While higher doses may be required to achieve benefits in some individuals, caution is advised to increase dosing slowly and divide the total daily dose into multiple smaller doses.

 

In the management of long term opioid tolerance, there are no studies to guide treatment regimens. Theoretically, supplementing with DXM serves to suppress the development of opioid tolerance but given that clinically significant opioid tolerance (and opioid-induced hyperalgesia and central sensitization) may take months, usually years to evolve it is difficult to measure benefit of treatment. One might conjecture that if any pain benefit is noted during the onset of treatment over the first few weaks, there may be an argument to maintain treatment to suppress long term changes from evolving.

 

References:

Dextromethorphan – Overviews

  1. QTc Prolongation Due to Dextromethorphan
  2. The Emerging Role of NMDA Antagonists in Pain Management – 2011
  3. Repurposing psychiatric medicines to target activated microglia in anxious mild cognitive impairment and early Parkinson’s disease – 2016

 

Dextromethorphan – Pain

  1. NMDA-receptor antagonist and morphine decrease CRPS-pain and cerebral pain representation – 2010
  2. The Emerging Role of NMDA Antagonists in Pain Management – 2011
  3. Dextromethorphan abuse – Clinical effects and management – 2009
  4. Dextromethorphan – A Review of N-methyl-D-aspartate Receptor Antagonist in the Management of Pain – 2007
  5. The role of dextromethorphan in pain control. – 2000
  6. The Use of NMDA-Receptor Antagonists in the Treatment of Chronic Pain – 2000
  7. Effects of dextromethorphan and oxycodone on treatment of neuropathic pain in mice – 2015
  8. Dextromethorphan as a potential neuroprotective agent with unique mechanisms of action. 2007  – PubMed – NCBI
  9. Analgesic effect of dextromethorphan in neuropathic pain. 2004 – PubMed – NCBI
  10. Pharmacologic Treatments for Neuropathic Pain

 

Dextromethorphan – Diabetic Peripheral Neuropathy (DPN)

  1. Dextromethorphan and Memantine in Painful Diabetic Neuropathy and Postherpetic Neuralgia – Efficacy and Dose-Response Trials – 2002
  2. Analgesic effect of dextromethorphan… [Acta Anaesthesiol Scand. 2004] – PubMed – NCBI
  3. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. 1997 – PubMed – NCBI
  4. Pharmacologic Treatments for Neuropathic Pain
  5. A Study of Potential Pharmacokinetic and Pharmacodynamic Interactions between Dextromethorphan:Quinidine and Memantine in Healthy Volunteers – 2012

 

Dextromethorphan – Opioid Tolerance

  1. The use of NMDA-receptor antagonists in the trea… [Clin J Pain. 2000] – PubMed – NCBI
  2. NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats. – PubMed – NCBI
  3. A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients – 2002
  4. Effects of Dextromethorphan on reducing methadone dosage in opium addicts undergoing methadone maintenance therapy: A double blind randomized clinical trial – 2011
  5. Dextromethorphan attenuated inflammation and combined opioid use in humans undergoing methadone maintenance treatment. 2012 – PubMed – NCBI
  6. A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment – 2015
  7. Low doses of dextromethorphan attenuate morphine-induced rewarding via the sigma-1 receptor at ventral tegmental area in rats. 2011 – PubMed – NCBI
  8. Co-administration of dextromethorphan with morphine attenuates morphine rewarding effect and related dopamine releases at the nucleus accumbens. 2003 – PubMed – NCBI

 

Dextromethorphan – Melatonin

  1. Melatonin prevents morphine-induced hyperalgesia and tolerance in rats -role of protein kinase C and N-methyl-D-aspartate receptors – 2015
  2. A COMBINED EFFECT OF DEXTROMETHORPHAN AND MELATONIN ON NEUROPATHIC PAIN BEHAVIOR IN RATS – 2009

 

Dextromethorphan – Nuedexta (Dextromethorphan with Quinidine)

  1. Review of Dextromethorphan 20 mg:Quinidine 10 mg (NUEDEXTA®) for Pseudobulbar Affect – 2014
  2. A Study of Potential Pharmacokinetic and Pharmacodynamic Interactions between Dextromethorphan:Quinidine and Memantine in Healthy Volunteers – 2012
  3. Evaluation of the reinforcing and subjective effects of heroin in combination with dextromethorphan and quinidine – 2011

 

Dextromethorphan – Abuse

  1. Dextromethorphan abuse – Clinical effects and management – 2009
  2. Robo-Tripping – Dextromethorphan Abuse and its Anesthetic Implication – 2014

 

Dextromethorphan – Pharmacokinetics and Genetics

  1. Pharmacokinetics of dextromethorphan and dextrorphan: a single dose comparison of three preparations in human volunteers. – PubMed – NCBI
  2. Pharmacokinetics of dextromethorphan and metabolites in humans – influence of the CYP2D6 phenotype and quinidine inhibition – 1995
  3. Comparison of the Effects of Dextromethorphan, Dextrorphan, and Levorphanol on the Hypothalamo-Pituitary-Adrenal Axis – 2004
  4. A Study of Potential Pharmacokinetic and Pharmacodynamic Interactions between Dextromethorphan:Quinidine and Memantine in Healthy Volunteers – 2012

 

Dextromethorphan – Toxicity

  1. QTc Prolongation Due to Dextromethorphan
  2. Dextromethorphan psychosis, dependence and physical withdrawal. 2005 – PubMed – NCBI

 

Dextromethorphan – Opioid Withdrawal

  1. The Therapeutic Effect of Adding Dextromethorphan to Clonidine for Reducing Symptoms of Opioid Withdrawal – A Randomized Clinical Trial – 2013

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