NMDA (N-Methyl-D-Aspartate) Receptor Antagonists

Medication Names:

Propoxyphene (Darvon®), Methadone, Ketamine

On Label Use:

Propoxyphene is a weak, short acting opioid analgesic

Methadone is a strong, long acting opioid analgesic

Ketamine is a dissociative anesthetic

Pain Use:

Propoxyphene is a mild NMDA receptor antagonist. It may also be useful at the end of downward titration of stronger opioids to prevent withdrawal.

Methadone is used as an opioid, but has mild NMDA receptor antagonist properties. It is the only strong opioid that has this quality.

Ketamine is used in oral preparations, IV delivery systems, in skin preparations via Organogel® and other delivery methods. Organogel® delivery can be compounded in various percentages. This seems to be the safest and best tolerated delivery system. It is useful against nerve pain and windup pain. This medication is best left to pain specialists

Therapeutic Benefit:

These medications can block NMDA glutamate receptors and decrease the wind-up pain so typical of chronic intractable pain. Wind-up causes an amplification of the incoming pain signal at the level of second degree neurons in the dorsal horn of the spinal cord. By blocking these receptors, not only is wind-up pain decreased, but tolerance to opioid medications can also be decreased. Ketamine has the added effect of blocking sodium channels.

Dose Range:

Propoxyphene and Methadone have no set dose ranges, but should be titrated up to effectiveness, versus side effect.

Ketamine has a very narrow therapeutic range when it is systemically absorbed. Organogel skin preparations appear to be quite safe with concentrations ranging from 1% to 15%. It should be applied to the affected area 2 to 3 times daily, until effective, then lowered to once daily.


All of these medications should be titrated up and watched for side effects.

Side Effects:

Propoxyphene- nausea, vomiting, drowsiness, irritability, loss of energy, constipation

Methadone- Dry mouth, blurred vision, drowsiness, constipation, urinary retention, forgetfulness, confusion,excessive perspiration, peripheral vasodilation, peripheral edema, depressed testosterone levels, and depression are among the more common side effects. Respiratory depression is less common, but quite serious and needs to be taken seriously. Euphoria is a side effect that makes these medications high risk for abuse, by drug addicts. The rate of addiction in patients without a history of addictive behavior is small. Physiologic dependency develops with regular use. Overdose can cause respiratory failure, obtundation, circulatory collapse and death.

Drug Interactions:

Additive problems of drowsiness, forgetfulness and confusion may occur with other CNS active medications.

Methadone and Amitriptyline should not be used together, due to potential cardiac arrhythmia problems.

Dependency or Abstinence Syndrome:

This is a significant issue with Propoxyphene and Methadone.. Even after a few weeks of regular use, these medications should be tapered off and not stopped abruptly. The first symptom of abstinence is increased pain. The next symptoms are goosebumps, chills, nausea, diarrhea, confusion, hallucinations and general feelings of flu-like symptoms. This can run from mild to severe and is generally not life threatening.

Dependency problems are a major issue, hence the schedule 2 nature of these medications. On the other hand these are the most useful medications in treating acute and chronic pain and as such should not be avoided because of fear of addiction in ones patients. If a physicians feel that their patient is an addict, but needs opioids, they should enlist the help of an Addictionologist in treating this group of patients. For other patients, physiologic dependency will develop with regular use of opioids, but this is easily managed by the treating physician.





Bay Area Pain Medical Associates provides the information as a guideline for physicians interested in up to date knowledge about the treatment of pain in their patients. We provide this as a public service without endorsing any specific treatment. Much of the medication used in managing pain is for "off label" use. Physicians using these medication are responsible for researching their efficacy, side effects, therapeutic benefits, interactions, titration and cessation, before deciding whether to use them in their practice. While we have provided information on these subjects, we do not feel this should serve as a substitute for looking up medications in standard texts and resources. When medications are left out of dosing, titration, drug interaction and side effect categories, it is because we do not think they should be used by anyone except for pain specialists.