Orphenadrine

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Orphenadrine
Systematic (IUPAC) name
N,N-dimethyl-2-[(2-methylphenyl)- phenyl-methoxy]-ethanamine
Identifiers
CAS number 83-98-7
ATC code M03BC01 N04AB02
PubChem 4601
DrugBank APRD00097
Chemical data
Formula C18H23NO 
Mol. mass 269.381 g/mol
Pharmacokinetic data
Bioavailability 90%
Protein binding 95%
Metabolism Hepatic demethylation
Half life 13-20 hours[1]
Excretion Renal and biliary
Therapeutic considerations
Pregnancy cat.

B2(AU) C(US)
Legal status

POM(UK) ℞-only(US)
Routes Oral, intravenous, intramuscular

Orphenadrine (Norflex®, Disipal®, Banflex®, Flexon® and others) is an anticholinergic and NMDA receptor antagonist [1]drug belonging to the ethanolamine class of antihistamines. This drug was invented in 1951 in France and made in the United States and Canada by Parke-Davis and other companies including 3M. It is a skeletal muscle relaxant which also has antihistamine, antispasmodic, analgesic , and local anaesthetic actions. The analgesic effect is both direct and indirect, viz., working as a potentiator of many other analgesics, both peripheral- and centrally-acting -- making it a good alternative to Neurotin® as an adjuvant analgesic for chronic pain management.

Contents

[edit] Uses

Orphenadrine is used to treat muscle injuries, skeletal muscle tension and rigidity secondary to afflictions such prolapsed discs and degenerative soft tissue disease especially in the lower back, neck, and joints. and other causes of muscle spasms, to potentiate the action of opioid analgesics against moderate to severe neuropathic pain, and it is also used to treat Parkinson's disease.

Orphenadrine is also a component of various preparations against headaches of various types especially tension and histamine headaches.

The effect on neuropathic pain, which is also in many cases generated by cyclobenzaprine (Flexeril®), atropine, scopolamine, hyoscyamine, trazadone, the antihistamines, and chemically related drugs like dicyclomine, a.k.a. dicycloverine, (Bentyl®), trihexyphenidyl (Artane®), first-generation tricyclic antidepressants such as amitriptyline, and other similar drugs, are said by many patients to seem to "help the painkillers find the pain". A direct analgesic effect of orphenadrine comes from relaxing painful muscle spasms as well as central antimuscarinic (atropine-like anticholinergic, see below) action and possibly its local anaesthetic effects.

[edit] Preparations

Orphenadrine is available almost invariably as the citrate and hydrochloride salts. The molecular weight of the orphenadrine hydrochloride is 305,85, compared to 461,50 for the citrate, and 269,38 for the free base. The citrate salt of orphenadrine (Norflex®, Banflex®, Flexon®, X-Otag®) is most often used for muscle spasms as well as headaches and similar problems, and the hydrochloride (Disipal® and Mephenamin®) is used, often as injection, for Parkinson's disease. At least for the latter use, the citrate and hydrochloride salts are not interchangeable, especially since the citrate is quite irritating when injected and the lower molecular weight of the hydrochloride contributes to faster and more complete CNS penetration.

In the United States and Canada, orphenadrine citrate is supplied as 100 mg controlled-release tablets, 100 mg immediate-release tablets, 60 mg immediate-release tablets, and 30 mg/ml solution for injection. Orphenadrine is also available mixed with aspirin, paracetamol, caffeine, and/or codeine in some countries such as Canada. Orphenadrine citrate tablets are a prescription item in the United States and over the counter in Canada; this drug is used less in Europe at this time but where it is available it tends to be over the counter and should be orderable by your local chemist under Section 76 of the Schengen Treaty if you are within the European Union and possibly the remainder of Central Europe.

[edit] Duration of effects

Orphenadrine is the preferred skeletal muscle relaxant in many cases as it is less likely to produce the long-lasting side effects of cyclobenzaprine and is not a benzodiazepine. Depending on individual metabolism, cyclobenzaprine and the benzodiazepines with active metabolites can cause residual sedation often termed hangover, residual anticholinergic effects like dry mouth, increased sensitivity to light, and other problems. Furthermore, the agents, cyclobenzaprine in particular, seem to hang in the system for days after the last dose was taken. Diazepam (Valium®) is often used for severe cases of muscle spasm and with a metabolic half life of 66 hours, has effects which can be detected by the patient up to as long as 10 days after the last dose depending on a number of factors. Other benzodiazepines used for this purpose outside of the United States, tetrazepam (Mylostan®) have shorter half lives and fewer active metabolites (diazepam has at least eight active metabolites, some of which are three or four steps removed from diazepam) and nitrazepam (Mogodon®) is even better in this respect.

[edit] Dosage and delivery

The muscle-relaxant and analgesic dose of orphenadrine is 100 mg when it is a 12-hour extended release tablet or 60 or 100 mg q8h immediate-release. The dose in Parkinson's Disease is 60 mg via the oral, intramuscular, or intravenous route. According to patients for both muscle spasm and Parkinson's Disease, the alternative routes for administration via the mouth (sublingual or buccal) or other transmucosal routes do not appear to impart any therapeutic advantage. Orphenadrine extended-release tablets can ostensibly be taken as-us by the rectal route as can MS-Contin®, MST Continus®, Vendal Retard® and similarly-constructed tablets of other drugs. (This property of said morphine products is known by many in the medical field as a work-around in cases where swallowing problems or severe vomiting which ejects anything administered by mouth is present; some or all the manufacturers of the tablets do seem to be acquainted with this method.)

[edit] Mechanism

The action of orphenadrine against muscle spasm and the pain produced by it, neuropathic pain, and the extrapyramidal effects of Parkinson's disease and treatments thereof, are the result of orphenadrine's moderate anticholinergic activity, which is about 58% the antimuscarinic strength of atropine. Orphenadrine is also an ethanolamine class antihistamine and most closely related to diphenhydramine (Benadryl®).

[edit] Side effects

Orphenadrine has the side effects of these antihistamines in large part, except that stimulation is somewhat more common and orphenadrine generates a slight yet durable euphoria in a large percentage of patients. Also in common with many antihistamines, and beyond its above-mentioned more or less direct analgesic actions, orphenadrine has analgesic-sparing (potentiating) effects on many centrally-acting analgesics such as codeine, dihydrocodeine, hydrocodone, and others as discussed below. Orphenadrine itself can be potentiated by the antihistamines hydroxyzine (Atarax®), a common opioid potentiator, as well as the pheniramine series of alkylamine antihistamines, viz. chlorpheniramine (Chlor-Trimeton®), dexchlorpheniramine (Polaramine®), brompheniramine (Dimetapp®), dexbrompheniramine (Drixoral®), pheniramine (Naphcon®), deschlorpheniramine, &c. Tripelennamine (PBZ®, Pyribenzamine®, Pelamine®) also has this effect, and of course orphenadrine's closest chemical relatives, the ethanolamine antihistamines including diphenhydramine, dimenhydrinate, bromdiphenhydramine, clemastine, doxylamine, carbinoxamine, and phenyltoloxamine will have additive effects when taken with orphenadrine. Antihistamines related to hydroxyzine like cyclizine and meclizine are also good potentiators of both opioids and orphenadrine.

As indicated above, orphenadrine generates a unique mild to moderate yet very durable and long-lasting euphoria in many patients. The euphoria is the result not of direct receptor activation in the CNS (à la nicotine and narcotics and possibly benzodiazepines) but rather direct changes in dopamine and acetylcholine levels, and does not appear to cause physical dependence or tolerance. Furthermore, the nature of the effect does really give the drug any but the most marginal of abuse liabilities (similar to some antihistamines) in the final analysis, and the result of repeated supertherapeutic doses is unpleasant, much like atropine. All the effects of orphenadrine do, none the less, increase the ability of just about any regimen of drugs for pain relief to stop and prevent suffering, as opposed to purely the pain stimulus considered without the cascade of secondary and tertiary effects of noxious stimulation of nerves and the unique properties of chronic pain of various aetiologies.

Euphoria is not an "adverse effect" -- from whatever source, it certainly helps in the healing process by reducing the effects of distress and fear in cases of continuous severe to extreme pain. Dysphoria is a potential side effect of opioids caused by activation of the kappa and delta opioid receptors as well as other parts of the central nervous system such as fluctuating norepinephrine levels, and is seen especially opioid mixed agonist-antagonist drugs such as the benzomorphan family (representative drug: pentazocine), but also pure agonists like morphine, hydromorphone, pethidine, methadone, and fentanyl. Orphenadrine is believed by many people, patients especially, to weaken, eliminate, and/or pre-empt the dysphoria via a mechanism which is not completely understood at this point although it is possible that it has to do with its action at NMDA receptors. Other NMDA receptor antagonists have been demonstrated to have weaken opioid withdrawal syndromes.[2]

As a further benefit, orphenadrine directly combats the effects of the histamine release in the body which many opioids, codeine and its close relatives in particular, tend to cause.

[edit] References

  1. ^ Labout JJ, Thijssen C, Keijser GG, Hespe W. "Difference between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man." European Journal of Clinical Pharmacology. 1982;21(4):343-50. PubMed
  2. ^ Ji D, Sui Z, Ma Y, Luo F, Cui C, Han J (2004). "NMDA receptor in nucleus accumbens is implicated in morphine withdrawal in rats". Neurochem Res 29 (11): 2113-20. PMID 15662845. 

[edit] External links

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Muscle relaxants (M03)
Peripherally acting Alcuronium, Atracurium, Cisatracurium, Dimethyltubocurarine, Doxacurium chloride, Fazadinium bromide, Gallamine, Hexafluronium, Mivacurium chloride, Pancuronium, Pipecuronium bromide, Rocuronium bromide, Suxamethonium, Tubocurarine, Vecuronium
Centrally acting Baclofen, Carisoprodol, Chlormezanone, Chlorzoxazone, Cyclobenzaprine, Febarbamate, Mephenesin, Methocarbamol, Orphenadrine, Phenprobamate, Phenyramidol, Pridinol, Styramate, Tetrazepam, Thiocolchicoside, Tizanidine, Tolperisone
Directly acting Dantrolene
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