Orphenadrine is most often used against pain and muscle spasm of various aetiologies including lumbago, sciatica, 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 analgesics. Orphenadrine is in many cases helpful against migraine and cluster headaches and is also used for treating some aspects of Parkinson's Disease 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 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 (Am J Psychiatry 114:1113–1115, June 1958)
Like many first-generation antihistamines and chemically-similar anticholinergics, orphenadrine can also cause excitement and insomnia, particularly in children and the elderly.
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.
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, trazodone, 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 neither antagonised nor 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.
A protocol for treating chronic pain and overall suffering by a combination of orphenadrine (cyclobenzaprine can be used but may prove inferior to orphenadrine in many respects), chlorpheniramine (or especially dexchlorpheniramine), caffeine, and dihydrocodeine or variants using other antihistamines and/or opioids such as hydrocodone, codeine, nicocodeine or similar opioid drugs all combined with paracetamol and/or NSAIDs. Small doses of ephedrine can be added to the caffeine for the purpose of increasing the analgesic efficacy of the opioid and reducing the sedative effect.
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.
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, 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 where single-ingredient and combination products are available over the counter. It is available over the counter in the Philippines as Norgesic (35mg Orphenadrine Citrate/450mg Paracetamol) and Norgesic Forte (50mg Orphenadrine Citrate/650mg Paracetamol) from 3M Pharmaceuticals. Orphenadrine is not available at this time in Japan, Slovenia, Croatia, China, France and Spain.
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.
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 in 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. Patients given hydromorphone and orphenadrine simultaneously report increased efficacy and duration of action of both agents, reduction of nausea, insomnia, and boosted euphoria to a level greater than the sum of its parts. The itching notable with codeine, dihydrocodeine, morphine and the like are also lessened or eliminated.
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 weakened opioid withdrawal syndromes. Clonidine is another drug that has these effects, although usually much stronger that orphenadrine.