Orphenadrine

Orphenadrine (sold under the brand names Norflex^®, Mephenamin^®, Disipal^®, Banflex^®, Flexon^®, Biorphen^®, Brocasipal^®, and others) is an antihistamine drug used to treat pain, muscle spasms and other symptoms of injury, and other problems. It is also used for treating some aspects of Parkinson's Disease.

In addition to muscle-relaxant and antihistaminergic effects, orphenadrine has significant antispasmodic, direct analgesic, and weak to moderate local anaesthetic actions. It also produces drowsiness and can have mild sedative and anxiolytic effects.

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History

This drug was first synthesised in the late 1940s in Europe and patented in the United States by Parke-Davis in July 1951. Currently, orphenadrine preparations are made in the United States and Canada by Parke-Davis and other companies including 3M.

Chemistry

Orphenadrine is a methylated derivative of diphenhydramine (Benadryl, Sominex, Nytol, etc.), and thus belongs to the ethanolamine family of antihistamines. It is produced by reacting dimethylaminoethanol with 2-methylbenzhydryl chloride. 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 and an NMDA receptor antagonist [1]. The action of orphenadrine against muscle spasm and the pain produced by it, pain produced independent of muscle spasm, 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 works by reducing muscle spasm and pain of varying etiologies and types, acute pain of injury and other causes as well as chronic and recurring acute pain syndromes producing nociceptive and/or neuropathic pain. It can be used as the main analgesic/muscle relaxant in cases of, for example, sports injuries, or as an atypical (adjuvant) analgesic and/or adjunct to typical analgesics such as opioids and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and for reduction of some histamine-related side effects of opioids, especially codeine and its semi-synthetic derivatives.

Orphenadrine exerts its effects both peripherally and in the central nervous system (CNS). In this latter respect, is similar to the chemically-unrelated drug nefopam as being a centrally-acting but non-opioid analgesic. Rather than binding to receptors as do opioids, benzodiazepines, seritonergic stimulants and the like, the central effect is the result of a change in the dopamine:acetylcholine ratio in the CNS because like other anticholinergics, it modifies dopamine and acetylcholine levels. Orphenadrine can also have a more comprehensive effect in both acute and chronic pain -- i.e. working against suffering -- in that the same effect also produce slight to moderate euphoria that lasts many hours and which is, for the above-given reasons, not the potential basis of addiction and abuse. Another reason for this drug's lack of habituation potential would be that the result of repeated supertherapeutic doses and/or significantly shortened dosage intervals is unpleasant, producing side effects much like those of atropine.

Orphenadrine is similar to other antihistamines in having analgesic-sparing (potentiating) effects on many opioids, thereby reducing the amount of narcotic painkiller needed in a particular case, e.g. breakthrough pain mitigation and overall titration of the painkiller dose. Orphenadrine also counters side-effects of opioids such as itching, facial flushing and other histamine-mediated symptoms.

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

The effect on neuropathic pain, which is also in many cases generated by cyclobenzaprine (Flexeril^®), atropine, scopolamine, hyoscyamine, trazadone, many first-generation 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.

The adjuvant analgesic effect of orphenadrine is not antagonised or directly duplicated by some other drugs used for this purpose, such as baclofen (Lioresal^®), clonidine (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, 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 (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 (Cymbalta^®) is contraindicated for whatever reason. Orphenadrine has fewer side effects than many first-generation anti-depressants, cyclobenzaprine, trazadone, clonidine, 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 60 mg tablets and 30 mg/ml solution for injection.

Orphenadrine is also available mixed with aspirin, paracetamol, caffeine, and/or codeine 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. Orphenadrine is not available at this time in Japan, Slovenia, Croatia, China, the Philippines, France and Spain.

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.

Euphoria is a side effect but not necessarily an "adverse effect" -- it may help in the healing process by reducing the effects of distress and fear in cases of continuous severe to extreme pain. This effect can also be of assistance in reducing or wiping out dysphoria which can be the result of other drugs used in treatment of chronic pain.

Dysphoria is a potential side effect of opioids caused by many mechanisms, including accumulation of metabolites of some opioids and other medications, the 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 less frequently pure agonists like morphine, hydromorphone, dihydrocodeine, dihydromorphine, nicomorphine, methadone, and fentanyl; pethidine and its chemical relatives especially. Orphenadrine may reduce this dysphoria by multiple actions.

Last but not least, orphenadrine may have yet another effect with respect to opioids: a clonidine-like effect on withdrawal symptoms useful for abrupt "cold turkey" cessation or accelerated tapers. Other NMDA receptor antagonists have been demonstrated to have weaken opioid withdrawal syndromes.^[2] Clonidine is another drug that has these effects, usually much stronger that orphenadrine.

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 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.

References

• Appleton & Langes Nursing Drug Guide, 2003
• Merck Index, 13th Edition
• AEGSP-WSMI Report on Availability of Selected Ingredients (21 August 2001) EU Table and World Table, PDF files retrieved 15 October 2001; some entries updated by press reports & other sources.

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.