How One May Obtain Significant Relief Pain With Over the Counter (OTC) Meds – Using Dextromethorphan

NOTE – many drugs could be effected by treatment below (and potentially dangerously) and so this should be supervised by your doctor or your pharmacist -especially if on Warfarin. There are rare cases of Dextromethorpan “Benylin cough syrup” dependence mentioned here but cases were usually people with widespread dependency drug issues.

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In the USA, a combination of Dextromethorphan and a drug to prevent its metabolism (quinidine) may have significant non-narcotic pain relieving potential though inhibition of NMDA receptors. It can be easily reproduced with DM cough capsules and grafefruit juice.
DM has had painkilling effects – a recent review is here:

CNS Drug Rev. 2007 Spring;13(1):96-106.
Dextromethorphan: a review of N-methyl-d-aspartate receptor antagonist in the
management of pain.
Siu A, Drachtman R.

OK – they don’t say much. Their abstract is:

Abstract

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.

Old Studies Find Dose required Not Tolerated
Earlier, there was an unflattering article about DM but that was with high doses and no inhibition of breakdown – side effects made it unusable:

Isr Med Assoc J. 2000 Sep;2(9):708-10.
Dextromethorphan in chronic pain: a disappointing update.
Ben-Abraham R, Weinbroum AA.  free article here  (click view file)
A recent article found DM helped neuropathic pain, but one had to take too much to get these effects.

Acta Anaesthesiol Scand. 2004 Mar;48(3):328-36.
Analgesic effect of dextromethorphan in neuropathic pain.
Carlsson KC, Hoem NO, Moberg ER, Mathisen LC. abstract here

However, a recent discovery found you can get around the excessive dose problems by taking concomitantly a breakdown inhibitor:

Drug called Zenvia is a combination of Dextromethorphan 30 mg and quinidine 10 mg has recently got FDA approval for “pseudobulbar palsy” in MS where there is inappropriate crying. Trials on the way to get indication for diabetic neuropathy.

News release re this here:

http://www.drugs.com/nda/zenvia_100430.html

Pain circuits use NMDA receptors to transmit their signals and the floodgates of these receptors are torn open by persistent barrage of chronic pain signals. Blockage of these receptors by IV ketamine, a general anesthetic, can give some pain relief for up to weeks but has nasty side-effects. Confirming my belief that some depression is a form of chronic pain, two (once a week) ketamine infusions can give relief of chronic depression resistent for up to a week as well:

Arch Gen Psychiatry. 2006 Aug;63(8):856-64.
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK.
free article here
– but that is a whole talk in itself.
Dextromethorphan is just a cough suppressant but has NMDA receptor blockage effects. It is available in 15 mg gelcaps that are supposed to last 8 hours (at least Robitussin brand). Quinidine was an IV med used to try and stabilize heart rhythms but was found not to be very useful and is no longer used.

Quinidine inhibits the breakdown of DM by inhibiting enzymes in the liver – the Cytochrome P450-CYP2D6 to be specific. Depending if you are good or bad liver metabolizer, this could mean your liver breakdown rates could be cut in half or substantially more (you still pee some in your urine). It would usually require 200 mg or more of DM for significant NMDA blockade; with liver blockers, you only need half or less of that.

To get that blockade out of DM 15 mg cough capsules you would need  13+ capsules/day – people are going to think you are a cough syrup junky, you will have too many side effects,  and it will cost to much.
However, there are other liver blockers out there – first check if you are on any – if you are, then you are set though you might need less than usual of the other drug as well.
Much is summarized here:
Concise Review of the Cytochrome P450s and their Roles inToxicology
Curtis J. Omiecinski,*,1 Rory P. Remmel,† and Vinayak P. Hosagrahara*.
Toxicological Sciences 48 151-9, 1999
free article here
DM breakdown Inhibiting drugs include:
– Fluoxetine (old prozac) – re chronic pain, used in combination with amitriptyline in fibromyalgia – or maybe could be stated if comorbid depression.

– Fluvoxamine (Luvox) 50- 100 mg – an older antidepressant that could be used as a sleep aid – cuts DM needs in half as per here:
Clin Pharmacol Ther. 1998 Sep;64(3):257-68.
Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as
determined by phenotyping.
Kashuba AD, Nafziger AN, Kearns GL, Leeder JS, Gotschall R, Rocci ML Jr, Kulawy
RW, Beck DJ, Bertino JS Jr  abstract here

And also re DM here:

Journal of Clinical Psychopharmacology: June 1998 – Volume 18 – Issue 3 – pp 198-207
Determinants of Interindividual Variability and Extent of CYP2D6 and CYP1A2 Inhibition by Paroxetine and Fluvoxamine In Vivo
Ozdemir, Vural MD, PhD; Naranjo, Claudio A. MD; Shulman, Richard W. MD, FRCP(C); Herrmann, Nathan MD, FRCP(C); Sellers, Edward M. MD, PhD, FRCP(C); Reed, Ken PhD; Kalow, Werner MD abstract here

Paroxetine (paxil) – though recent studies have downplayed its use as an antidepressant, still functions as a good anti-anxiety agent.

Quinine – used to be used more for restless legs.

Cymbalta might be on the list but its levels seem to be the one most effected so might be tricky. Trazodone is mentioned too, but might be more the same problem.
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Having said that, Grapefruit juice is found to block DM breakdown:- it appears to operate more at the gut breakdown level than the liver.
Life Sciences 71 (2002) 1149–1160
The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: The role of gut CYP3A and P-glycoprotein Marika Pasternyk Di Marco a,d, David J. Edwards b, Irving W. Wainer,
Murray P. Ducharme  free article here

First day they gave 200 mls (6.7 ounces) grapefruit juice. The viable alternative was a bitter variety of orange juice – 200 ml seville orange juice – fresh squeezed as no one would make that otherwise.
Even though there was a placebo day in between, inhibition seems to carry over so suspect could take half the amount of juice thereafter.  -so maybe 6 oz day one and 3 oz thereafter
There are grapefruit pills out there and they might do as well. Anybody know??
I would suggest one – two capsules of DM cough capsules 3-4 times daily plus the fruit juice and see.  – maybe two at bedtime and in morning with only 1 lunch and supper.

People with resistant depression could get relief as well as per this patent using DM in depression:

PHARMACEUTICAL COMPOSITIONS FOR TREATING DEPRESSION, ANXIETY AND NEURODEGENERATIVE DISORDERS – They used the dextromethorphan and quinidine combination

Use of Ketamine Infusion Test
[First I would like to mention that a group who just reviewed the literature and didn’t actually try the test itself has decreed it has limited efficacy:

Intravenous infusion tests have limited utility for selecting long-term drug therapy in patients with chronic pain: A systematic review
Cohen, S.P.a b e , Kapoor, S.G.c , Rathmell, J.P.
Anesthesiology Volume 111, Issue 2, August 2009, Pages 416-431 abstract here
This could be called “evidence based medicine” or it could be called “I won’t say it works until you absolutely make me.” Statistically speaking that means the specificity (when they say it works, they’re right – is high; but the sensitivity – given that people with chronic pain have so many problems, just dealing with one factor will not show much even if it does help  eg. – working the trapezius tip muscles might not show much results until one deals with the C5 facet (facet injection relieves 50% of trap tips). There are some ethical issues involved in this lack of sensitivity and the one liner at the end of evidenced based reviews that says more research needs to be done does NOT absolve researchers from this ethical obligation – shame on them. Benjamin Disraeli said “There are three kinds of lies: lies, damned lies, and statistics.” Using an approach with poor sensitivity hardly gives people a clear picture. For example, only 40% of cases will respond to DM and now that breakdown blockers are being used, it will be more tolerable for them. Combining DM with a nighttime dose of ketamine might magnify results, however systematic review of isolated old use may suggest it’s no use…

Sorry – had to get that off my chest….
I would have been more impressed if they had at least tried it to see…]

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NMDA receptor inhibition is an unused option up to now. One inhibitor, memantine, has had mediocre effects but it wasn’t a very good blocker. Results could be mediocre here to but only time will tell. It is possible that combining it with small doses of memantine or ketamine might bolster the effect.

There is a way to tell which patients might benefit from DM – a low dose IV ketamine infusion:

J Pain. 2006 Jun;7(6):391-8.
The intravenous ketamine test predicts subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients.
Cohen SP, Verdolin MH, Chang AS, Kurihara C, Morlando BJ, Mao J.  abstract here
Protocol was:

– IV of midazolam 0.25- 0.5 mg to prevent dysphoria through 20 guage needle;>75 kg needs higher dose
– after a 5 minute wait, IV ketamine 0.1 mg/kg (8 mg for 80 kg subject) over 7 minutes
– 30 minutes of some confusion is pretty universal.
– response was a > 50% reduction in pain.

1/2 of Fibromyalgia patients responded positively; they were given DM 0.5- 1 mg/kg three times daily (40-80 mg DM for 80 kg patient) – starting with lower dose.

77% of those who responded to ketamine got > 50% reduction in pain.

Responders on average pre – 5.8/10 after DM – average 1.7/10 with a mean daily dose of 147 mg DM

The same approach has been found helpful in neuropathic pain except patients had to be >67% better after ketamine infusion:
Anesth Analg. 2004 Dec;99(6):1753-9, table of contents.

The intravenous ketamine test: a predictive response tool for oral dextromethorphan treatment in neuropathic pain.
Cohen SP, Chang AS, Larkin T, Mao J. free article here
using that criterian 90% will respond well to DM while 80% who do not will not respond to DM

25 cases included:
7 failed back surgery syndrome (FBSS) with a radicular component
5 complex regional pain syndrome type I
4 peripheral neuropathy
2 central pain
2 postherpetic neuralgia

40% responded to ketamine and 90% of those responded to DM; 1 patient (4%) did not respond to ketamine but did to DM
bottom line is 36 + 4 = 40% were responders to DM with neuropathic pain

WHY NON-RESPONDERS?
Comment  – Big question I have is why did 60% not respond to Ketamine infusion/ dextromethorphan. The answer is obvious to me – No one bothered to deal with peripheral myofascial pains and subclinical nerve entrapments (cluneal for back, in scar for post herpetic, tarsal tunnel for diabetics). I call it  “Didn’t anybody bother to turn out the lights?” All these fancy procedures – steroid epidurals, facet blocks, radiofrequency and no one spends time getting rid of garbage peripheral triggers left behind – it is stupid and infantile (No orthopedic surgeon has ever massaged out a piriformis probably because that is not what they do so their scope becomes infantily narrow. I think they need a good talking from their mothers…).

Just sending them to a massage therapist will not do because too many of them are afraid they might hurt the patient and that fact will get back to the doctor. I tried to get physiotherapy to do it but was told it is too hard.  Recently, I have been doing 2-3 piriformis victims a day – each require 10-20 minutes therapeutic massage to work out the patient – a very specific technique discussed here:

How Should One Investigate Chronic Back Pain and What about the Back Muscles?

1/3 of those with a piriformis will have a Quadratus lumborum “friend” that needs working as well.

Since I have been using an activator manipulation device, I find that most back pains have facet issues relieved temporarily by manipulation – almost trivially so – though they come back. This leads to the issue of prolotherapy to prevent the obvious facet rotations/lockings that one can see on flexion/extension exams with fingers over facets at a level. What people will respond to that needs to be better worked out as well.
Well, so much for that. Unfortunately, The anesthetist in the town bowed out of doing ketamine infusions saying there is a hospital clampdown on its use. So one is left to try DM and see.

One thing that dose seem possible to augment effect would be to give the DM and supplement with a nighttime dose of ketamine orally or intranasal. The isomer version mentioned in recent article does not appear to exist commercially. Anyone have any experience with ketamine? – what bedtime dose would be worth given a try?
I have one Bipolar case that is resistant to antidepressants and MAO inhibitors but has shown some response to DM (though at this point could be placebo). I have not yet tried DM but have one patient on methotrexate that has peripheral neuropathy and would be good candidate. It was mentioned above:

in: CNS Drug Rev. 2007 Spring;13(1):96-106.
Dextromethorphan: a review of N-methyl-d-aspartate receptor antagonist in the
management of pain.
Siu A, Drachtman R.
That DM  useful “in the treatment of methotrexate-induced neurotoxicity.”

I hope Dextromethorphan gives some people hope – but think long term use must be supervised by your doctor.