Accurate Education – 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.

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.

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.

Dextromethorphan and Opioid Withdrawal

Dextromethorphan Metabolism

Dextromethorphan and Genetics

 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.

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.

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 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.

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.