Orphenadrine

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Orphenadrine

Orphenadrine (sold under the brand names Norflex, Mephenamin, Disipal, Banflex, Flexon, Biorphen, Brocasipal, and others) is an anticholinergic

Anticholinergic

An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central nervous system and the peripheral nervous system....
drug

Drug

A drug, broadly speaking, is any chemical substance that, when absorbed into the body of a living organism, alters normal bodily function....
of the ethanolamine antihistamine

Antihistamine

An H1 antagonist is a histamine antagonist of the histamine H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergy....
class with prominent CNS and peripheral actions used to treat painful muscle spasm and other symptoms and conditions as well as some aspects of Parkinson's Disease

Parkinson's disease

Parkinson's disease is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech, as well as other functions....
. It is closely related to diphenhydramine

Diphenhydramine

Diphenhydramine hydrochloride , trade name Benadryl as produced by McNeil Laboratories a division of J&J, or Dimedrol outside the U.S....
and therefore related other drugs used for Parkinson's like benztropine

Benztropine

Benzatropine mesilate , benztropine mesylate, or benztropine marketed as Cogentin, is an anticholinergic medication principally used for the treatment of:...
and trihexyphenidyl

Trihexyphenidyl

Trihexyphenidyl, also known as Benzhexol, is an antiparkinsonian drug of the antimuscarinic class. Chemically, it is a tertiary amine with alcohol, Benzene, and Cyclohexane moieties....
and is also structurally related to nefopam

Nefopam

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Encyclopedia

Orphenadrine (sold under the brand names Norflex, Mephenamin, Disipal, Banflex, Flexon, Biorphen, Brocasipal, and others) is an anticholinergic

Anticholinergic

An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central nervous system and the peripheral nervous system....
drug

Drug

A drug, broadly speaking, is any chemical substance that, when absorbed into the body of a living organism, alters normal bodily function....
of the ethanolamine antihistamine

Antihistamine

Parkinson's disease

Diphenhydramine

Benztropine

Benzatropine mesilate , benztropine mesylate, or benztropine marketed as Cogentin, is an anticholinergic medication principally used for the treatment of:...
and trihexyphenidyl

Trihexyphenidyl

Nefopam

Nefopam is a centrally-acting but non-opioid analgesic drug of the benzoxazocine chemical class, developed in the early 1970s. It is widely used, mainly in European countries, for the relief of moderate to severe pain as an alternative to opioid analgesic drugs....
, a centrally-acting yet non-opioid analgesic. The combination of anticholinergic effects and CNS penetration make orphenadrine useful for pain of all aetiologies including pain from radiculopathy

Radiculopathy

Radiculopathy is not a specific condition, but rather a description of a problem in which one or more nerves are affected and do not work properly ....
, muscle pain, headaches, and many others. Some patients report that it feels like orphenadrine and similar drugs help both NSAIDs and opioids find the pain.

Orphenadrine is most often used against pain

Pain

Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm....
and muscle spasm of various aetiologies including lumbago, sciatica

Sciatica

Sciatica is a set of symptoms including pain that may be caused by general compression and/or irritation of one of five nerve roots that give rise to the sciatic nerve, or by compression or irritation of the sciatic nerve itself....
, and injury. It is quite useful against allergic symptoms and other histimine-related effects, such as those from hayfever, other allergies, and histamine release from many opioid

Opioid

An opioid is a chemical substance that has a morphine-like action in the body. The main use is for analgesia. These agents work by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract....
analgesics. Orphenadrine is in many cases helpful against migraine

Migraine

Migraine is a neurology syndrome characterized by altered bodily perceptions, headaches, and nausea. Physiologically, the migraine headache is a neurological condition more common to women than to men....
and cluster headaches and is also used for treating some aspects of Parkinson's Disease

Parkinson's disease

Parkinson's disease is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech, as well as other functions....
including side effects caused by the main therapy in place. Where available for prescription compounding, orphenadrine can also be prepared for topical administration and works slightly better than diphenhydramine for this purpose.

The orphenadrine salt used for Parkinsonism is the hydrochloride, whereas the muscle relaxant tablet are the citrate, and manufacturers' descriptions of orphenadrine indicate that the salts are not interchangeable; one reason may be that the citrate can be irritating when injected.

Euphoria

Euphoria

Euphoria or euphoric may refer to:* Euphoria , an emotional and mental state Defined as a sense of great elation and wellbeing* 4-Methyl-aminorex , a stimulant drug with effects comparable to methamphetamine...
is an effect reported by many patients and orphenadrine has been investigated for use against depression, as first reported in June 1958 in the American Journal of Psychiatry.

Like many first-generation antihistamines and chemically-similar anticholinergics, orphenadrine can also cause excitement and insomnia, particularly in children and the elderly.

Orphenadrine also works on smooth muscle in a manner identical to that of dicyclomine

Dicyclomine

Dicyclomine is an anticholinergic that blocks muscarinic acetylcholine receptor. Dicyclomine is known as dicycloverine hydrochloride in the UK....
(Bentyl) and will impact Irritable Bowel Syndrome

Irritable bowel syndrome

Irritable bowel syndrome , also called spastic colon, is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any organic cause....
in a similar fashion.

History

This drug was first synthesised in the late 1940s in Europe and the citrate and hydrochloride were both patented in the United States by Parke-Davis

Parke-Davis

Parke-Davis is a subsidiary of the pharmaceutical company Pfizer Inc.. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history....
in July 1951. Currently, orphenadrine preparations are made in the United States and Canada by Parke-Davis and other companies including 3M

3M Company , formerly Minnesota Mining and Manufacturing Company until 2002, is an United States multinational corporation Conglomerate corporation with a worldwide presence....
. Known as Disipal, orphenadrine HCl was advertised by the Riker company for Parkisonism, low back pain, and having a useful anti-depressant effect which helps in treating such conditions -- http://www.decodog.com/inven/MD/md30554.jpg

Chemistry

Orphenadrine is a methylated derivative

Derivative (chemistry)

In chemistry, a derivative is a Chemical compound that is formed from a similar compound or a compound that can be imagined to arise from another compound, if one atom is replaced with another atom or group of atoms....
of diphenhydramine

Diphenhydramine

Diphenhydramine hydrochloride , trade name Benadryl as produced by McNeil Laboratories a division of J&J, or Dimedrol outside the U.S....
(Benadryl, Sominex, Nytol, etc.), and thus belongs to the ethanolamine

Ethanolamine

Ethanolamine, also called 2-aminoethanol or monoethanolamine , is an organic chemical compound that is both a primary amine and a primary alcohol ....
family of antihistamines. It is produced by reacting dimethylaminoethanol with 2-methylbenzhydryl chloride. The 2-methylbenzhydryl chloride can be formed via a Grignard reaction

Grignard reaction

The Grignard reaction, named after the French chemist Fran?ois Auguste Victor Grignard, is an organometallic chemistry chemical reaction in which alkyl- or aryl-magnesium halides , act as nucleophiles, attack electrophilic carbon atoms that are present within polar bonds to yield a carbon-carbon bond , thus altering hybridization about the r...
. The free base has a molecular weight of 269.38 and an empirical formula of C₁₈H₂₃NO. The molecular weight of orphenadrine hydrochloride is 305.85, and 461.50 for the citrate.

Pharmacology

Orphenadrine is an anticholinergic

Anticholinergic

An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central nervous system and the peripheral nervous system....
and an NMDA

NMDA

NMDA is an amino acid derivative acting as a specific agonist at the NMDA receptor, and therefore mimics the action of the neurotransmitter glutamate on that receptor....
receptor antagonist . The action of orphenadrine against muscle spasm and the pain produced by it, pain produced independent of muscle spasm, neuropathic

Neuropathy

Neuropathy is a medical term describing disorders of the nerves of the peripheral nervous system It is usually considered equivalent to peripheral neuropathy....
pain

Pain

Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm....
, and the extrapyramidal effects of Parkinson's Disease and treatments thereof, are the result of orphenadrine's moderate anticholinergic

Anticholinergic

An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central nervous system and the peripheral nervous system....
activity.

Uses

Orphenadrine is used to treat muscle

MUSCLE

MUSCLE is public domain, multiple sequence alignment software for protein and nucleotide sequences.MUSCLE is integrated into UGENE bioinformatics tool as a plugin....
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

Pain

Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm....
, and it is also used to treat Parkinson's disease

Parkinson's disease

Parkinson's disease is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech, as well as other functions....
.

Orphenadrine is also a component of various preparations for use against headaches of various types especially tension and histamine headaches. It is also helpful in many cases of fibromyalgia

Fibromyalgia

Fibromyalgia , meaning muscle and connective tissue pain , is a disorder classified by the presence of chronic widespread pain and a heightened and painful response to gentle Somatosensory system ....
.

The effect on neuropathic pain, which is also in many cases generated by cyclobenzaprine

Cyclobenzaprine

Atropine

Atropine is a tropane alkaloid extracted from deadly nightshade , jimsonweed , Mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a hard drug with a wide variety of effects....
, scopolamine

Scopolamine

Scopolamine, known by the names levo-duboisine and hyoscine, is a tropane alkaloid Medication with muscarinic antagonist effects. It is obtained from plants of the family Solanaceae , such as henbane, jimson weed and Angel's Trumpets , and corkwood ....
, hyoscyamine

Hyoscyamine

Hyoscyamine, pronounced hi-oh-SYE-uh-meen, is a chemical compound, a tropane alkaloid. It is the levorotary isomer to atropine. It is a secondary metabolite found in certain plants of the Solanaceae family, including henbane, mandrake , jimsonweed , and deadly nightshade ....
, trazodone

Trazodone

Trazodone is a psychoactive compound with sedative, anxiolytic, and antidepressant properties. The various manufacturers claim that the antidepressant becomes active in the first week of therapy....
, many first-generation antihistamines, and chemically related drugs like dicyclomine

Dicyclomine

Dicyclomine is an anticholinergic that blocks muscarinic acetylcholine receptor. Dicyclomine is known as dicycloverine hydrochloride in the UK....
, a.k.a. dicycloverine, (Bentyl), trihexyphenidyl

Trihexyphenidyl

Trihexyphenidyl, also known as Benzhexol, is an antiparkinsonian drug of the antimuscarinic class. Chemically, it is a tertiary amine with alcohol, Benzene, and Cyclohexane moieties....
(Artane

Artane

Artane may refer to:* Artane, Dublin, a suburb of Dublin, Ireland* Artane, a brand-name for the drug trihexyphenidyl used to treat Parkinson's disease...
), first-generation tricyclic antidepressants such as amitriptyline

Amitriptyline

Amitriptyline hydrochloride is a tricyclic antidepressant Medication. It is a white, odorless, crystalline compound which is freely soluble in water; it is usually dispensed in tablet form....
, 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.

The adjuvant analgesic effect of orphenadrine is neither antagonised nor directly duplicated by some other drugs used for this purpose, such as baclofen

Baclofen

Baclofen is a derivative of gamma-aminobutyric acid primarily used to treat spasticity.It is an agonist specific to mammalian but not fruit fly GABA B receptors....
(Lioresal), clonidine

Clonidine

Clonidine is a direct-acting alpha-2 adrenergic receptor adrenergic agonist....
(Catapres) and others, or gabapentin (Neurontin) so the effects are largely additive if used in combination (same goes for side effects, however), and such medication protocols need close monitoring by a physician especially when other centrally-acting drugs are being used to treat the pain. Cyclobenzaprine

Cyclobenzaprine

Cyclobenzaprine is a tricyclic antidepressant compound that is used clinically as a long-acting muscle relaxant and analgesic. It is marketed as Flexeril , and also as Fexmid ....
, tricyclic anti-depressants, and antihistamines do, however, have additive side effects but little improvement in the clinically desired effects in that they duplicate and compete with each other in this respect.

Orphenadrine can be used in protocols for treating chronic and/or recurring pain as an alternative to gabapentin

Gabapentin

Gabapentin is a Gamma-aminobutyric_acid analogue. It was originally developed for the treatment of epilepsy, and currently, gabapentin is widely used to relieve pain, especially neuropathic pain....
(Neurontin) as an adjuvant analgesic for management of chronic pain with a neuropathic component amongst those who cannot tolerate the side effects of gabapentin; this is also the case for patients in whom duloxetine

Duloxetine

Duloxetine is a serotonin-norepinephrine reuptake inhibitor effective for the treatment of major depressive disorder , general anxiety disorder , pain related to diabetic neuropathy, fibromyalgia and stress urinary incontinence ....
(Cymbalta) is contraindicated for whatever reason. Orphenadrine has fewer side effects than many first-generation anti-depressants, cyclobenzaprine, trazadone, clonidine

Clonidine

Clonidine is a direct-acting alpha-2 adrenergic receptor adrenergic agonist....
, and other drugs used in chronic pain states.

Preparations

The citrate salt of orphenadrine is available as Norflex, Banflex, Flexon, and X-Otag, and the hydrochloride salt is available as Disipal and Mephenamin.

In the United States and Canada, orphenadrine citrate is supplied as 100 mg controlled-release tablets, 100 mg immediate-release tablets, and 60 mg immediate-release tablets. Orphenadrine hydrochloride is supplied as 50 and 60 mg tablets, a 10 mg/ml oral solution and 30 mg/ml solution for injection.

Orphenadrine is also available mixed with aspirin

Aspirin

Aspirin , also known as acetylsalicylic acid , is a salicylate medication, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication....
, paracetamol

Paracetamol

Paracetamol or acetaminophen is a widely used over-the-counter drug analgesic and antipyretic . It is commonly used for the relief of fever, headaches, and other minor aches and pains, and is a major ingredient in numerous common cold and Influenza remedies....
, caffeine

Caffeine

Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a psychoactive stimulant drug and a mild diuretic. Caffeine was discovered by a German chemist, Friedrich Ferdinand Runge, in 1819....
, and/or codeine

Codeine

Codeine or methylmorphine is an opiate used for its analgesic, Cough medicine and Antidiarrhoeal properties. It is by far the most widely used opiate in the world and probably the most commonly used drug overall according to numerous reports over the years by organizations such as the World Health Organization and its League of Nations...
in many places. All orphenadrine preparations require a prescription in the United States and the various oral forms are over the counter in Canada; orphenadrine is also available in many European and Pacific Rim countries (including Australia), by prescription in all of them except Belgium, Mexico and Canada where single-ingredient and combination products are available over the counter. It is available over the counter in the Philippines as Norgesic (35 mg Orphenadrine Citrate/450 mg Paracetamol

Paracetamol

Dosage and delivery

The muscle-relaxant and analgesic dose of orphenadrine is 100 mg when it is a (theoretical) 12-hour extended release tablet or 60 or 100 mg q8h immediate-release. In common with extended release tablets of other drugs, Norflex extended-release tablets more frequently than not require dosing every six or eight hours. It is not clear if the extended-release form of orphenadrine is more effective on a milligram basis than the immediate-release formulations.

The dose to be used in therapy for 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, and this would seem to include the rectal route as well.

Side effects

Orphenadrine has the side effects of the antihistamines in large part; notably, stimulation is somewhat more common than with other related antihistamines, and is especially common in the elderly. Common side effects are therefore dry mouth, dizziness, drowsiness, restlessness, insomnia, constipation, urine retention, orthostatic hypotension, and euphoria. The drowsiness and similar side effect tend to resolve within the first three to seven days of therapy.

Interactions

The cautions and contraindications that apply to other antihistamines in its group apply. Dry mouth should be treated to prevent trouble with teeth. One should avoid driving and operating heavy machinery until such time as the effect is known. Constipation

Constipation

Constipation, costiveness, or irregularity, is a condition of the digestive system in which a person experiences hard feces that are difficult to expel....
is possible but usually less severe than that caused by opioids. Aside from brief rebound stiffness in some patients, orphenadrine does not produce detectable cessation symptoms after therapy is discontinued.

External links

National Center for Biotechnology.