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Drugs of Today (Barcelona, Spain : 1998) Sep 2008A new agent containing a combination of dextromethorphan (DM) and quinidine (Q) is currently under development for the treatment of pseudobulbar affect (PBA). PBA is a... (Review)
Review
A new agent containing a combination of dextromethorphan (DM) and quinidine (Q) is currently under development for the treatment of pseudobulbar affect (PBA). PBA is a disorder of emotional regulation, characterized by uncontrollable outbursts of laughing and/or crying that are disproportionate to the emotions being experienced. The pathophysiology of PBA is currently unknown, although the disorder is thought to occur exclusively in the setting of neurological disease. The most influential theory on PBA posits that emotional outbursts are being generated autonomously in the brain stem due to loss of regulatory control by the frontal lobe. Although rarely life-threatening, PBA can have significant impact on patient quality of life, and thus merits treatment. There are currently no approved treatments for PBA. Several agents have been found to be effective in small placebo-controlled trials and case series, with the most commonly used agents being tricyclic antidepressants and selective serotonin reuptake inhibitors. Both these treatments are inexpensive and relatively low-risk, although the quality and quantity of data available on their efficacy are not optimal. DM has several pharmacological mechanisms of action relevant to the brain. It is an N-methyl-D-aspartate (NMDA) receptor antagonist, which prompted investigators to study its potential for slowing progression in amyotrophic lateral sclerosis (ALS), where glutamate toxicity is thought to be a factor. The combination agent DM/Q was developed to slow the metabolism of DM by P450 2D6 enzymes in the liver. DM/Q was not effective in slowing ALS progression, but patients noted that it helped to control their emotional outbursts, suggesting it might be useful as a treatment for PBA. DM is also a sigma-1 receptor agonist. These receptors are widely distributed in the brain, but probably most heavily in the limbic system, suggesting that DM may exert its emotion-controlling effects via these receptors. The endogenous ligands for sigma-1 receptors are not altogether known, although they appear to include gonadal steroids. DM/Q was recently shown to be effective in reducing the severity of PBA in two large studies of ALS and multiple sclerosis, which are probably the most common neurological settings. These are the largest treatment studies of PBA ever done. The agent was safe and relatively well tolerated. Further studies are being conducted to see if efficacy can be maintained with lower doses of quinidine. If DM/Q is approved by the U.S. Food and Drug Administration for treatment of PBA, it would be the first agent approved for this purpose. Currently, the antidepressants are probably the most attractive pharmacologic options for treatment of PBA. The choice of whether to use DM/Q in this setting will likely depend on individual patient factors as well as cost.
Topics: Antidepressive Agents, Tricyclic; Clinical Trials as Topic; Dextromethorphan; Drug Combinations; Humans; Pseudobulbar Palsy; Quinidine; Selective Serotonin Reuptake Inhibitors
PubMed: 19137121
DOI: 10.1358/dot.2008.44.9.1258664 -
Journal of the American Pharmacists... 2009To describe the epidemiology, patient presentation, and clinical management associated with dextromethorphan (DM) abuse. (Review)
Review
OBJECTIVE
To describe the epidemiology, patient presentation, and clinical management associated with dextromethorphan (DM) abuse.
DATA SOURCES
PubMed/Medline search using terms dextromethorphan and abuse through July 2008, bibliographies of selected publications, epidemiology tracking databases.
STUDY SELECTION
By the authors.
DATA EXTRACTION
English language-published review articles, clinical trials, and case reports that described the epidemiologic and toxicologic profile of DM were included.
DATA SYNTHESIS
DM is a relatively inexpensive and easily accessible over-the-counter (OTC) medication intended for use as an antitussive. Increasingly, illicit use of the drug has been reported. At clinical doses, the drug produces few adverse effects. However, when abused in large quantities (>2 mg/kg), the drug has been associated with a dissociative effect similar to those described by ketamine and phencyclidine abusers. Massive ingestions of the drug may be associated with untoward effects, including tachycardia, hypertension, and respiratory depression. Overdose symptoms may also be associated with coformulated products such as antihistamines and sympathomimetic amines. Management is primarily supportive. Naloxone has been used to manage DM toxicity but with conflicting reports of effectiveness.
CONCLUSION
Recent reports indicate that DM is often abused by individuals seeking its dissociative effects. Clinicians should be aware of the abuse potential of DM. Pharmacists might be particularly cognizant of the risks involved with DM abuse as they control OTC access to the drug.
Topics: Animals; Dextromethorphan; Humans; Opioid-Related Disorders; Substance Abuse Detection
PubMed: 19289333
DOI: 10.1331/JAPhA.2009.08091 -
The Annals of Pharmacotherapy Nov 1999To review the use of dextromethorphan for the treatment of painful diabetic neuropathy. (Review)
Review
OBJECTIVE
To review the use of dextromethorphan for the treatment of painful diabetic neuropathy.
DATA SOURCES
MEDLINE and EMBASE searches for studies using dextromethorphan to manage diabetic neuropathy were conducted from 1966 to 1999 and 1980 to 1999, respectively.
DATA SYNTHESIS
Peripheral neuropathy is a common manifestation of diabetic patients. Many classes of medications have been investigated to treat this condition, including N-methyl-D-aspartate inhibitors. A review of studies using dextromethorphan to manage diabetic neuropathy was performed.
CONCLUSIONS
There are insufficient safety and efficacy data to justify the use of dextromethorphan for treating painful diabetic neuropathy. Further clinical trials are needed.
Topics: Dextromethorphan; Diabetic Neuropathies; Excitatory Amino Acid Antagonists; Humans; Randomized Controlled Trials as Topic; Receptors, N-Methyl-D-Aspartate
PubMed: 10573324
DOI: 10.1345/aph.18296 -
Trends in Pharmacological Sciences Dec 1989Dextromethorphan is one of the most widely used non-opioid cough suppressants, representing the active ingredient in several over-the-counter antitussive formulations.... (Review)
Review
Dextromethorphan is one of the most widely used non-opioid cough suppressants, representing the active ingredient in several over-the-counter antitussive formulations. It does not possess the CNS pharmacology of other opiates in humans (i.e. analgesia, respiratory depression, abuse liability or psychotomimetic properties), but since the discovery in 1981 of high affinity recognition sites in brain for dextromethorphan a unique neuropharmacological profile has emerged for this relatively innocuous drug. Anticonvulsant and neuroprotective properties have been demonstrated, and treatment with dextromethorphan has been shown to improve the cerebrovascular and functional consequences of global cerebral ischemia. Frank Tortella and colleagues review the CNS pharmacology of dextromethorphan, its possible involvement with NMDA or sigma-receptors, and the potential clinical importance of this old 'new' drug.
Topics: Animals; Dextromethorphan; Humans; Levorphanol; Nervous System
PubMed: 2694543
DOI: 10.1016/0165-6147(89)90050-3 -
The American Journal on Addictions Aug 2016Dextromethorphan (DXM) in combination with antihistamines and/or pseudoephedrine is widely available as an over-the counter remedy commonly used for relief of colds and... (Review)
Review
BACKGROUND
Dextromethorphan (DXM) in combination with antihistamines and/or pseudoephedrine is widely available as an over-the counter remedy commonly used for relief of colds and cough. In supra-therapeutic amounts, DXM has psychoactive effects. These cough preparations have been adopted by many young users of recreational drugs for these effects.
OBJECTIVES
This paper aims to highlight the increasingly prevalent practice of Robotripping, review pharmacokinetic and dynamic data and discuss potential tolerance and withdrawal from the substance as well as treatment modalities.
METHODS
A Medline search (1985-2015) for literature concerning the DXM was conducted. This was supplemented by references gleaned from recent epidemiological surveys and credible online sources to ensure most up to date information is gathered.
CONCLUSION AND SCIENTIFIC SIGNIFICANCE
Use in amounts exceeding those recommended, a practice known as "Robotripping", may result in a toxidrome of psychomotor agitation, hallucinations and paranoia best characterized as Intoxication Delirium. Increasing misuse places greater numbers at risk. Providers should be alert to such presentations and be aware of methods for managing the symptoms. With chronic use, tolerance and withdrawal has been noted along with prolonging psychiatric sequelae. (Am J Addict 2016;25:374-377).
Topics: Antitussive Agents; Dextromethorphan; Humans; Illicit Drugs; Nonprescription Drugs; Substance-Related Disorders
PubMed: 27288091
DOI: 10.1111/ajad.12389 -
The Journal of Allergy and Clinical... Aug 1998
Topics: Adult; Anaphylaxis; Antitussive Agents; Dextromethorphan; Drug Hypersensitivity; Female; Humans; Molecular Structure
PubMed: 9723677
DOI: 10.1016/s0091-6749(98)70101-0 -
Life Sciences 1989There is increasing evidence that sigma ligands and dextromethorphan (DM) bind to at least one common high-affinity site. DM and other antitussives do not produce... (Review)
Review
There is increasing evidence that sigma ligands and dextromethorphan (DM) bind to at least one common high-affinity site. DM and other antitussives do not produce psychotomimetic effects. This suggested that sigma ligands may produce their characteristic effects through another site, and prompted us to review critically the literature on the side effects of sigma opiates. Contrary to what is generally accepted, the dysphoric and psychotomimetic side effects of sigma opiates are mediated by the levo-and not by the dextrorotatory isomers. Moreover, these effects are unequivocally naloxone-reversible. Therefore, the current version of the "sigma receptor", with high affinity for the dextrorotatory sigma opiates, cannot explain the psychotomimetic effects of the levorotatory enantiomers. Thus, neither the "sigma ligands" nor its newly defined "receptor" are involved in the psychotomimetic effects of sigma opiates. Further experimentation with more selective drugs and with a combination of different methods will be necessary to identify the different binding sites, and to establish their physiological role and therapeutic potential.
Topics: Animals; Dextromethorphan; Endorphins; Hallucinogens; Humans; Levorphanol; Piperidines; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Stereoisomerism
PubMed: 2556614
DOI: 10.1016/0024-3205(89)90510-9 -
Annals of Clinical and Translational... Aug 2023No efficacious treatments exist to improve or prolong bulbar functions of speech and swallowing in persons with amyotrophic lateral sclerosis (pALS). This study...
OBJECTIVE
No efficacious treatments exist to improve or prolong bulbar functions of speech and swallowing in persons with amyotrophic lateral sclerosis (pALS). This study evaluated the short-term impact of dextromethorphan/quinidine (DMQ) treatment on speech and swallowing function in pALS.
METHODS
This was a cohort trial conducted between August 2019 to August 2021 in pALS with a confirmed diagnosis of probable-definite ALS (El-Escorial Criteria-revisited) and bulbar impairment (ALS Functional Rating Scale score ≤ 10 and speaking rate ≤ 140 words per minute) who were DMQ naïve. Efficacy of DMQ was assessed via pre-post change in the ALS Functional Rating Scale-Revised bulbar subscale and validated speech and swallowing outcomes. Paired t-tests, Fisher's exact, and χ tests were conducted with alpha at 0.05.
RESULTS
Twenty-eight pALS enrolled, and 24 participants completed the 28-day trial of DMQ. A significant increase in ALSFRS-R bulbar subscale score pre- (7.47 ± 1.98) to post- (8.39 ± 1.79) treatment was observed (mean difference: 0.92, 95% CI: 0.46-1.36, p < 0.001). Functional swallowing outcomes improved, with a reduction in unsafe (75% vs. 44%, p = 0.003) and inefficient swallowing (67% vs. 58%, p = 0.002); the relative speech event duration in a standard reading passage increased, indicating a greater duration of uninterrupted speech (mean difference: 0.33 s, 95% CI: 0.02-0.65, p = 0.035). No differences in diadochokinetic rate or speech intelligibility were observed (p > 0.05).
INTERPRETATION
Results of this study provide preliminary evidence that DMQ pharmacologic intervention may have the potential to improve or maintain bulbar function in pALS.
Topics: Humans; Amyotrophic Lateral Sclerosis; Dextromethorphan; Quinidine; Deglutition; Speech
PubMed: 37265174
DOI: 10.1002/acn3.51821 -
CNS Drug Reviews 2007Dextromethorphan (DM) is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, which is widely used as an antitussive agent. DM also prevents neuronal damage... (Review)
Review
Dextromethorphan (DM) is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, which is widely used as an antitussive agent. DM also prevents neuronal damage and modulates pain sensation via noncompetitive antagonism of excitatory amino acids (EAAs). DM has been found to be useful in the treatment of pain in cancer patients and in the treatment of methotrexate-induced neurotoxicity. Clinical studies with DM in cancer patients are reviewed in this article.
Topics: Animals; Clinical Trials as Topic; Dextromethorphan; Excitatory Amino Acid Antagonists; Humans; Pain; Receptors, N-Methyl-D-Aspartate
PubMed: 17461892
DOI: 10.1111/j.1527-3458.2007.00006.x -
The Neurologist Sep 2007Dextromethorphan (DM) is a widely-used antitussive. DM's complex central nervous system (CNS) pharmacology became of interest when it was discovered to be... (Review)
Review
BACKGROUND
Dextromethorphan (DM) is a widely-used antitussive. DM's complex central nervous system (CNS) pharmacology became of interest when it was discovered to be neuroprotective due to its low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonism.
REVIEW SUMMARY
Mounting preclinical evidence has proven that DM has important neuroprotective properties in various CNS injury models, including focal and global ischemia, seizure, and traumatic brain injury paradigms. Many of these protective actions seem functionally related to its inhibitory effects on glutamate-induced neurotoxicity via NMDA receptor antagonist, sigma-1 receptor agonist, and voltage-gated calcium channel antagonist actions. DM's protection of dopamine neurons in parkinsonian models may be due to inhibition of neurodegenerative inflammatory responses. Clinical findings are limited, with preliminary evidence indicating that DM protects against neuronal damage. Negative findings seem to relate to attainment of inadequate DM brain concentrations. Small studies have shown some promise for treatment of perioperative brain injury, amyotrophic lateral sclerosis, and symptoms of methotrexate neurotoxicity. DM safety/tolerability trials in stroke, neurosurgery, and amyotrophic lateral sclerosis patients demonstrated a favorable safety profile. DM's limited clinical benefit is proposed to be associated with its rapid metabolism to dextrorphan, which restricts its central bioavailability and therapeutic utility. Systemic concentrations of DM can be increased via coadministration of low-dose quinidine (Q), which reversibly inhibits its first-pass elimination. Potential drug interactions with DM/Q are discussed.
CONCLUSIONS
Given the compelling preclinical evidence for neuroprotective properties of DM, initial clinical neuroprotective findings, and clinical demonstrations that the DM/Q combination is well tolerated, this strategy may hold promise for the treatment of various acute and degenerative neurologic disorders.
Topics: Animals; Clinical Trials as Topic; Dextromethorphan; Humans; Nervous System Diseases; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Trauma, Nervous System
PubMed: 17848867
DOI: 10.1097/NRL.0b013e3180f60bd8