Opioids Adjuvants & Opioid Potentiators In Chronic Pain Control

[Nicomorphinist]

Orphenadrine, nefopam, chlorphenamine and caffeine taken together and on top of hydromorphone (rotated with ketobemidone and nicomorphine once or twice a year, and assorted other middling and strong narcotic analgesics for breakthrough pain), naproxen, and paracetamol seem to do a very good job of subtracting out both the burning and lightning-like pain and it actually feels like the orphenadrine in particular and perhaps the nefopam seem to help the analgesics find the pain. Tripelennamine helps IM/SC morphine, oxymorphone and so on work better as well.

I had a bad reaction to gabapentin when it was prescribed as an adjunct to morphine a long time ago, and I have noticed that the orphenadrine-nefopam-chlorphenamine-stimulant combinations (the chlorphenamine used to have phenylpropanolamine in it) actually is a better gabapentin than gabapentin, at least in my case.

The anticholinergic + opioid combination is an old tried and true method to combat especially neuropathic pain. With stimulants as well, both to prevent orthostatic hypotension and strengthen the pain killing effect, as well as reduce somnolence. Hence Brompton Mixture, Scophedal, Paracetamol with Codeine with caffeine in it and oncologists and chronic pain doctors writing for methylphenidate, dextroamphetamine, or, back in the day, pyrovalerone.

Which adjuvants and potentiators work best for folks here?

MOD EDIT: Please don't copy & paste D-F articles with embedded links to D-F in them

 

[Jekyl Anhydride]

NMDA NR2B specific antagonists, exemplified by ifenprodil, are known to potentiate opiates (Bernardi et al, 1996). The combination of the side-effects associated with the co-administration of NMDA antagonists and opiates (Hoffman et al, Pharmacol Biochem Behav. 2003) produces significantly more respiratory depression, and possibly more emesis and mental clouding, than either agent given alone.

CCK receptor antagonists such as proglumide have been demonstrated to reverse tolerance to opiates, reducing the dose of opiate required to produce analgesia (Kellstein et al, Pain; 1991 ). Consequently, proglumide has been demonstrated to boost opiate analgesia, meaning that a markedly reduced dose of opioid is required to achieve the same level of analgesia. This has been shown to occur, without any potentiation in respiratory depression (US-A-4576951 ) or any effect on the development of opiate dependence (Paneria et al., Brain Research; 1987).
The pharmacology of proglumide is mixed CCKA (gastrin) and CCKg antagonism, its anti-ulceration action being via the inhibition of the CCKA
receptor. Antagonism at the CCKg receptor has thus far been unexploited and is known to be involved in the development of tolerance to morphine analgesia

CA2542837A1 - The use of non-opiates for the potentiation of opiates - Google Patents

A non-opioid analgesic is used for the treatment of intermittent or episodic pain experienced by a patient undergoing chronic pain treatment with an opioid analgesic.

patents.google.com

Proglumide - an overview | ScienceDirect Topics

www.sciencedirect.com

 

[Nicomorphinist]

Nefopam in particular can be a lot of help to people who cannot tolerate codeine very well, who are in chronic pain and need a potentiator to help with nerve pain in particular . . . I have not heard of anything recently about any trials in the United States, but one of my nieces back there goes to a pain clinic associated with a university and was able to get her doctors to set up an N-of-1 trial of it where she takes the nefopam and they record all of the data and write it up; they are going to do the same thing with meptazinol afterwards. Still a long road, but this option is out there for people.

 

[ChemicallyEnhanced]

I take 8mg of Chlorphenamine with every opiate dosing. Mostly for the itching but it does have potentiating properties, too.
Does Nefopam actually potentiate opioids?? I used to be prescribed 3 Nefopam, three times a day. Never found it did anything for me, but wasn't on opiates at the time. Oh actually I was on methadone.

 

[Nicomorphinist]

I take 8mg of Chlorphenamine with every opiate dosing. Mostly for the itching but it does have potentiating properties, too.
Does Nefopam actually potentiate opioids?? I used to be prescribed 3 Nefopam, three times a day. Never found it did anything for me, but wasn't on opiates at the time. Oh actually I was on methadone.

Nefopam does potentiate opioids in general by apparently more that one method and has a lot in common with orphenadrine in this and other ways.

 

[ChemicallyEnhanced]

Nefopam does potentiate opioids in general by apparently more that one method and has a lot in common with orphenadrine in this and other ways.

Is Diphenhydramine is good as orphenadrine? (I believe they are like "cousins"). I've never known orphendarine to be available here.

I also take 50mg caffeine with my opiates.

I agree that Naproxen is great. I have degenerative osteo-arthritis in my knees from extreme over-use and it helps me walk a lot further than I otherwise could.

 

[Nicomorphinist]

Is Diphenhydramine is good as orphenadrine? (I believe they are like "cousins"). I've never known orphendarine to be available here.

I also take 50mg caffeine with my opiates.

I agree that Naproxen is great. I have degenerative osteo-arthritis in my knees from extreme over-use and it helps me walk a lot further than I otherwise could.

Orphenadrine is actually stimulating to a lot of folks and the euphoria is more marked than with diphenhydramine, and the clinical handbooks and the like mention that orphenadrine citrate (the most common, the muscle relaxant) and the hydrochloride (Disipal) have a euphoriant effect and this was part of the marketing of the product. Specifically, the antidepressant effect was said to help with various types of pain. as this was when tricyclic antidepressants were first coming out in the late 1940s and early 1950s, Orphenadrine and the TCAs do have structural and pharmacological properties in common. The tricyclic structure and other similar ones are found in anticholinergics of a number of classes, and indeed dicycloverine (Bentyl) and trihexyphenidyl (Artane, Sexy Trihexy) are used by scientists as active placebos when doing testing of new narcotic drugs.

Nefopam is also a very distant structural relative of the opioids pentazocine and phenazocine, but there are none of the dysphoric or hallucinogenic effects. This may explain why adding nefopam to Blue Velvet (morphine and tripelennamine) makes it more powerful as a euphoriant.

Diphenhydramine does have excellent narcotic potentiating effects , as well as having metabolic effects which help with the weaker opioids like codeine, DHC &c. The ethanolamine first-generation antihistamine which I my experience which does the most for narcotics is phenyltoloxamine, followed closely with doxylamine succinate. There are also halogenated diphenhydramine derivatives which are very useful in these cases, with bromdiphenhydramine (Ambrodyl) being a very good one.

Chlorphenamine and the other alkylamine antihistamines exhibit optical isomerism and for example, in some respects Polarimine (dexchrlorphenamine) has 20 times the effects of the racaemic mixture. Bromphenamine (Dimetapp) and dexbromphenamine (Drixoral) are also good potentiators. In addition to the eight halogenated pheniramine derivatives in racaemic and dextrorotary forms, there is the parent compound of the series, and despheniramine as well

The very best of the antihistamines for narcotic potentiation would be tripelennamine (Pyribenzamine and others), which is an ethylenediamine antihistamine,. Hydroxyzine and cyclizine, which are used for potentiation by doctors and pharmaceutical manufacturers are piperazine antihistamines and are very good too.

Tripelennamine and the piperidine first-generation antihistamine phenindamine (Nolahist, Thephorin) are actually good enough to create notable euphoria by themselves especially if injected.

 

[Jekyl Anhydride]

I still think Diphenhydramine along with several other 1st Gen antihistamines are crap for Codeine and Tramadol, and DHC as well due to the fact it kills CYP 450 2D6 which is what converts all the methylated morphine. Or O-DesmethylTramadol, even messing with the 3A4 levels that effect Phase II Glucuronidation. Which makes up the other half of codeine besides the smidge of demethylated morphine.

From KK's Codeine MT, the mod with the masters degree in Bio:

7. Interactions
As codeine is metabolized via CYP2D6 into morphine anything that inhibits this isozyme will lessen the effects of codeine. A list of CYP2D6 inhibitors includes:
- Antidepressants, i.e. fluoxetine, paroxetine, sertraline, duloxetine, citalopram and bupropion
- quinine and quinidine
- cimetidine
- antihistamines, i.e. promethazine, chlorphenamine, diphenhydramine, hydroxyzine

For Tramadol 2D6 is also essential:


For DiHydrocodeine it's also essential:

DHC and DHM displayed affinity that was twice as high as that of their 7,8-nonsaturated analogues (codeine and morphine). In conclusion, the O-demethylation of DHC leads to the formation of DHM and DHM-6-G, which displays the highest affinity for u-opioid receptors. This reaction depends on CYP2D6 enzyme activity.

https://www.karger.com/Article/PDF/326085

 

[checktest]

Tricyclics can work for some, though with side effects and limited efficacy for some conditions, not the best evidence. Desipramine was quite good for my shooting thoracic outlet nerve pain. Also along with a pulse of prednisone, but certainly that's not a long-term choice and was for an acute incident. I preferred ketoprofen to naproxen but it doesn't last as long and needed a prescription.

SNRIs and tramadol. I have a friend who had great benefit from duloxetine with her fibromyalgia and whatever else, though I think some studies overstated efficacy. Mianserin.

Carbamazepine has significant drug interactions and side effects but definitely does work for some neuropathies. Not a first choice.

 

[Jekyl Anhydride]

I'm really not a fan of Carbamazepine as is put my dad into a devolving arrhythmia with gabapentin until cardioversion with a defibrilator. But Gabapentin by itself or with Diclofenac topical was good. Ketoprofen wasn't bad either and better than Ibu or Naprox.

 

[ChemicallyEnhanced]

Orphenadrine is actually stimulating to a lot of folks and the euphoria is more marked than with diphenhydramine, and the clinical handbooks and the like mention that orphenadrine citrate (the most common, the muscle relaxant) and the hydrochloride (Disipal) have a euphoriant effect and this was part of the marketing of the product. Specifically, the antidepressant effect was said to help with various types of pain. as this was when tricyclic antidepressants were first coming out in the late 1940s and early 1950s, Orphenadrine and the TCAs do have structural and pharmacological properties in common. The tricyclic structure and other similar ones are found in anticholinergics of a number of classes, and indeed dicycloverine (Bentyl) and trihexyphenidyl (Artane, Sexy Trihexy) are used by scientists as active placebos when doing testing of new narcotic drugs.

Nefopam is also a very distant structural relative of the opioids pentazocine and phenazocine, but there are none of the dysphoric or hallucinogenic effects. This may explain why adding nefopam to Blue Velvet (morphine and tripelennamine) makes it more powerful as a euphoriant.

Diphenhydramine does have excellent narcotic potentiating effects , as well as having metabolic effects which help with the weaker opioids like codeine, DHC &c. The ethanolamine first-generation antihistamine which I my experience which does the most for narcotics is phenyltoloxamine, followed closely with doxylamine succinate. There are also halogenated diphenhydramine derivatives which are very useful in these cases, with bromdiphenhydramine (Ambrodyl) being a very good one.

Chlorphenamine and the other alkylamine antihistamines exhibit optical isomerism and for example, in some respects Polarimine (dexchrlorphenamine) has 20 times the effects of the racaemic mixture. Bromphenamine (Dimetapp) and dexbromphenamine (Drixoral) are also good potentiators. In addition to the eight halogenated pheniramine derivatives in racaemic and dextrorotary forms, there is the parent compound of the series, and despheniramine as well

The very best of the antihistamines for narcotic potentiation would be tripelennamine (Pyribenzamine and others), which is an ethylenediamine antihistamine,. Hydroxyzine and cyclizine, which are used for potentiation by doctors and pharmaceutical manufacturers are piperazine antihistamines and are very good too.

Tripelennamine and the piperidine first-generation antihistamine phenindamine (Nolahist, Thephorin) are actually good enough to create notable euphoria by themselves especially if injected.

Thanks for the info. I purposely got a prescription for Cyclizine when I read in one of the Trainspotting books (I think it was Skaglads) that it potentiates the euphoric effects of opioids. I knew my doctor wouldn't give it to for for that reason, though, so I'm prescribed it 3 times a day for positional vertigo.

 

[checktest]

JA- Sorry to hear that about your Dad. Yeah, Carbamazepine can be quite a scary drug, and certainly isn't a first line except for trigeminal neuralgia and some seizure disorders. Whatever sodium channel effects and various weirdness. I just wanted to mention a separate class of agent.

 

[Jekyl Anhydride]

Thanks ct. No they totally have their place and work well for some. He just got nurse Ratchett who saw it written down on the current meds list as a mistake from awhile back, and she insisted that lists never lie. Until his T waves were nearly inverted. ?

Speaking of Ca & Na channel blockers, Lamotrigene wasn't so bad and was far more compatible with gabapentin iirc. Too bad the days of the Las Vegas Cocktail are disappearing fast. Beats the hell out of antihistamine families or weak SNDRI's no longer sold.

 

[nznity]

Orphenadrine, nefopam, chlorphenamine and caffeine taken together and on top of hydromorphone (rotated with ketobemidone and nicomorphine once or twice a year, and assorted other middling and strong narcotic analgesics for breakthrough pain), naproxen, and paracetamol seem to do a very good job of subtracting out both the burning and lightning-like pain and it actually feels like the orphenadrine in particular and perhaps the nefopam seem to help the analgesics find the pain. Tripelennamine helps IM/SC morphine, oxymorphone and so on work better as well.

I had a bad reaction to gabapentin when it was prescribed as an adjunct to morphine a long time ago, and I have noticed that the orphenadrine-nefopam-chlorphenamine-stimulant combinations (the chlorphenamine used to have phenylpropanolamine in it) actually is a better gabapentin than gabapentin, at least in my case.

The anticholinergic + opioid combination is an old tried and true method to combat especially neuropathic pain. With stimulants as well, both to prevent orthostatic hypotension and strengthen the pain killing effect, as well as reduce somnolence. Hence Brompton Mixture, Scophedal, Paracetamol with Codeine with caffeine in it and oncologists and chronic pain doctors writing for methylphenidate, dextroamphetamine, or, back in the day, pyrovalerone.

Which adjuvants and potentiators work best for folks here?

MOD EDIT: Please don't copy & paste D-F articles with embedded links to D-F in them

Man this is totally off. topic but I love to read all of your posts, your lexis and vocabulary is just from another world. Outstanding, whenever I read one of your posts it's like reading a scientific paper Combined with a pinch of sarcasm and the exact amount of seriousness. Oh and all of your contributions are really good. Nicomorphinist for president ?.

 

[checktest]

Ah yes, the all knowing lists. Such a mess. I saw my GP for the first time in yeats, who was affiliated with the research hospital I went to (same EMR), and the nurse/MA wanted to reconcile my med list. Essentially something like You're on acetaminophen, mirtazapine, wellbutrin, parnate, methylphenidate, buspar, Brintellix, lithium, Namenda and ketamine, correct? I don't think my psych ever learned how to discontinue meds in the system, and the ketamine was just a research study. Hadn't been on some in years. And I never take acetaminophen on its own.

Soma was definitely a solid muscle relaxant and better than metaxolone for me. Not a fan of cyclobenzaprine. But yeah, not getting that any more from a lot of providers.

I don't know the current research state of TLR4 antagonists with opioids (tolerance, avoidance of hyperalgesia), but that was thought to be a possible reason for tricyclic and some antihistamine combinations in pain as well. I wonder how ibudilast would work. Come to think of it, I wonder how some of the other PDE inhibitors would balance for inflammatory and nerve pain. Tadalafil in diabetic neuropathy or something.

 

[Jekyl Anhydride]

Yes I found Soma, Oxycocone and some alprazolam to fix spasms rather well, making up the LV cocktail or The Holy Trinity for the Rec. users, but probably rarely, if ever to be seen again in this knee jerk reaction climate.

I know that ULDN or ultra low dose nalaoxone of naltrexone can make opioids much stronger, stop the stimulatory signaling and increase the inhibitory signalling of G Coupled Proteins that cause tolerance problems and hyperalgesia.

I'll have to do a bit of digging intoTLR4 antagonists, PDE5 inhibitors are all the rage but it's difficult to search for anything besides PDE5. "type-11 PDE isoenzyme has been associated with pain" was all I could get from a paywall abstract.

Back to the classics for now eh..

NMDA Antagonists, while old hat now, still seem to make me want to try a few weeks of Memantine.

NMDA antagonists for tolerance, a collection of the evidence and anecdotal reports

I tought id make this thread for those interested in using NMDA antagonists for drug tolerance. NMDAR and opioid tolerance: (PMID: 19806811) Development of morphine induced tolerance and withdrawal symptoms is attenuated by lamotrigine and magnesium sulfate in mice From these results it is...

www.bluelight.org

Something for a laugh:

Melatonin prevents morphine-induced hyperalgesia and tolerance in rats: role of protein kinase C and N-methyl-D-aspartate receptors

Morphine-induced hyperalgesia and tolerance significantly limits its clinical use in relieving acute and chronic pain. Melatonin, a pineal gland neurohormone, has been shown to participate in certain neuropsychopharmacological actions. The present study ...

www.ncbi.nlm.nih.gov

 

[checktest]

I'm on memantine right now (20 mg), and I do suspect it highly to have reduced pain that I should expect from a rotator cuff tear. Not quite the evidence base of ketamine for some pain conditions but much easier to get. I still wonder how much tolerance 'prevention' is overstated with NMDA antagonists.

Even a little magnesium could be beneficial.

MAGnesium-oral supplementation to reduce PAin in patients with severe PERipheral arterial occlusive disease: the MAG-PAPER randomised clinical trial protocol | BMJ Open

I'll wait to see what the trial says but at least the introduction has some relevant pain links.

Besides the opioid receptors, I wonder when other neuropeptide receptors will be targeted. Neuropeptide y y1 y2 and the like. I mean I know they are being looked at but of course the timelines can vary.

Tanezumab or whatever that anti-NGF ab is called passed some trials with middling results, but I don't think I would sign up for those right away.

I have a friend with chronic pain and fibromyalgia-esque symptoms who I still wonder if she has mast cell issues. Flushing, rashes, cycles. I mean her brother has mastocytosis, but yes. I wonder if people with strong reactions with opioid itching or chronic use would benefit from mast cell stabilizers like cromolyn say, versus copious amounts of antihistamines.

Mast cell-neural interactions contribute to pain and itch

Mast cells are best recognized for their role in allergy and anaphylaxis, but increasing evidence supports their role in neurogenic inflammation leading to pain and itch. Mast cells act as a “power house” by releasing algogenic and pruritogenic ...

www.ncbi.nlm.nih.gov

EDIT: goddamn melatonin

 

[Jekyl Anhydride]

Since you're on Memantine anyways, any opioids you take won't build any tolerance which might be kinda nice. I would love to try memantine just for the NMDA effect. Ketamine has such a short DOA and halflife to be of any effect for G coupled protein/adenyl cyclase "fixing".

Is there anything imparticular you dislike about it>

While mast cell technology is being used for things far beyond H1 release from opioids, as it's a short term condition vs Neurogenic problems where Auto-Immune disorders cause round the clock pruritus symptoms.

Some other things to look into: cromolyn , imatinib

One thing it has done for pain is in regards to Sickle Cell Disorder /Anemia, in mice so far.

We show that mast cell activation/degranulation contributes to sickle pain pathophysiology by promoting neurogenic inflammation and nociceptor activation via the release of substance P in the skin and dorsal root ganglion. Mast cell inhibition with imatinib ameliorated cytokine release from skin biopsies and led to a correlative decrease in granulocyte-macrophage colony-stimulating factor and white blood cells in transgenic sickle mice. Targeting mast cells by genetic mutation or pharmacologic inhibition with imatinib ameliorates tonic hyperalgesia and prevents hypoxia/reoxygenation-induced hyperalgesia in sickle mice. Pretreatment with the mast cell stabilizer cromolyn sodium improved analgesia following low doses of morphine that were otherwise ineffective. Mast cell activation therefore underlies sickle pathophysiology leading to inflammation, vascular dysfunction, pain, and requirement for high doses of morphine. Pharmacological targeting of mast cells with imatinib may be a suitable approach to address pain and perhaps treat SCA.

https://www.ncbi.nlm.nih.gov/pubmed/23775718/

So with Mast cells, in humans it looks like the bulk of the research is going to treat Neurogenic , neurovascular interactions ,

: Neurogenic inflammation involves a multicellular system involving neurovascular interactions in the skin and visceral organs.(31, 32) It involves the release of vasoactive and proinflammatory neuropeptides SP and calcitonin gene-related peptide (CGRP) from the sensitized peripheral nerve endings; this leads to vascular dilatation, plasma extravasation, leukocyte infiltration, and mast cell activation.(33, 34) Upon activation, mast cells release neuropeptides, histamine, and other algogenic mediators that stimulate nerve endings to release more neuropeptides, leading to a vicious cycle of mast cell activation and peripheral nerve sensitization further amplifying vascular leakage and neurogenic inflammation.(33, 35) This process leads to painful wheals and flares (redness and heat), pruritus, and edema, and further sensitizes sensory nerve endings.

Mast cell-neural interactions contribute to pain and itch

Mast cells are best recognized for their role in allergy and anaphylaxis, but increasing evidence supports their role in neurogenic inflammation leading to pain and itch. Mast cells act as a “power house” by releasing algogenic and pruritogenic ...

www.ncbi.nlm.nih.gov

Neuropeptides/ receptors are a birds nest of wires so to speak to configure and manipulate, hopefully they can get on it, godspeed to them::

At present about 100 different peptides are known to be released by different populations of neurons in the mammalian brain.[2] Neurons use many different chemical signals to communicate information, including neurotransmitters, peptides, and gasotransmitters. Peptides are unique among these cell-cell signaling molecules in several respects. One major difference is that peptides are not recycled back into the cell once secreted, unlike many conventional neurotransmitters (glutamate, dopamine, serotonin). Another difference is that after secretion, peptides are modified by extracellular peptidases; in some cases, these extracellular cleavages inactivate the biological activity, but in other cases the extracellular cleavages increase the affinity of a peptide for a particular receptor while decreasing its affinity for another receptor. These extracellular processing events add to the complexity of neuropeptides as cell-cell signaling molecules. Many populations of neurons have distinctive biochemical phenotypes. For example, in one subpopulation of about 3000 neurons in the arcuate nucleus of the hypothalamus, three anorectic peptides are co-expressed: α-melanocyte-stimulating hormone (α-MSH), galanin-like peptide, and cocaine-and-amphetamine-regulated transcript (CART), and in another subpopulation two orexigenic peptides are co-expressed, neuropeptide Y and agouti-related peptide (AGRP). These are not the only peptides in the arcuate nucleus; β-endorphin, dynorphin, enkephalin, galanin, ghrelin, growth-hormone releasing hormone, neurotensin, neuromedin U, and somatostatin are also expressed in subpopulations of arcuate neurons. These peptides are all released centrally and act on other neurons at specific receptors. The neuropeptide Y neurons also make the classical inhibitory neurotransmitter GABA

https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid

 

[checktest]

I don't seem to have any issues with the memantine, though I had a few leg cramps when I bumped up to 20. I was exercising a fair amount so I can't really say it wasn't that at the time. Sometimes I get a feeling in the back of my head of some pressure, but my blood pressure is/ was fine, and it passes. I guess some people really need to titrate it as they feel it is impairing, and perhaps in some ways when I started I was not quite as quick with some things, but the memantine helped overall. My memory and processing seem reasonable. I'm on other drugs though, so not an isolated judgment.

Yeah, oddly enough a family member has GI mastocytosis as well and does cromolyn sodium in little tubules. I remember reading a nature comm paper on it with Alzheimer's and was intrigued. This was a digression.

 

[cdin]

Black seed oil (nigella sativa) and proglumide have worked wonders for me. Also, it seems no one here has noted ULDN - ultra-low dose naltrexone - combats tolerance/extends pain relieving effect. Any time i take a painkiller I preload w 20 - 40mcg nalt.