Instituut voor Neuropathische Pijn

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Fenytoine voor centrale neuropathische pijnen

Centrale neuropathische pijn is zeer ernstig. Soms kan vrijwel het halve lichaam diepe pijn geven volgend op een herseninfarct rond de thalamus (syndrom thalamique) of op een dwarslaesie. Centrale neuropathische pijn is erg lastig te behandelen. Hier beschrijven we de resultaten van de behandeling met een oud anti-epileptisch middel dat vaak vergeten wordt: fenytoine.

Treatment of the painful, burning dysaesthesias which occasionally occur after thalamic infarction has been a particlarly vexing problem. Administration of a variety of psychotropic and analgesic drugs has yielded variable but generally impersistent and ineffective results. The improvement noted in some cases after stereotaxic lesions in thalamic nuclei or other parts of the sensory pathway has often been transient. The following two cases illustrate successful treatment of thalamic pain with phenytoin.

Zo begint de Amerikaanse neuroloog Cantor zijn betoog in het Britisch Medical Journal (1972).

Vervolgens beschrijft hij 2 gevallen die we hier weergeven, vanwege het belang ervan:

Patient 1

A 56-year-old man with hypertensive cardiovascular disease abruptly developed tingling paraesthesias in his left fingers which progressed over 24 hours to involve the arm and leg. In the next few weeks he developed progressively severe, persistent, painful dysaesthesias of the left hand and foot aggravated by touch. Examination of these areas showed a modest rise in pain threshold. Strong painful dysaesthesias occurred with tactile or pin stimuli. During his second week of treatment with 300 mg of phenytoin daily there was a progressive decrease of the dysaesthesias culminating in their disappearance. Phenytoin was discontinued one month later because of toxicity. Over the next 10 days the dysaesthesias progressively recurred as the toxic signs diminished. On 150 mg of phenytoin daily he noted no toxicity and a tolerable reduction of dysaesthesias.  

150 mg Fenytoine was dus werkzaam zonder al te veel bijwerkingen.

Patient 2

A 51-year-old man with hypertensive and atherosclerotic cardiovascular disease awoke with persistent tingling of the left face, hand, and foot. During the next few days the foot became normal. Increasingly severe burning sensations developedTreatment of diabetic neuropathy  in the hand and face. Examination showed an increased threshold to pin  Pain and touch stimuli on the face, and forearm. Tactile and pin stimulation evoked buming, dysaesthetic pain. Progressive improvement began on the sixth day of phenytoin treatment. One year later the dysaesthesias recurred when phenytoin was stopped. Reinstitution of treatment again caused alleviation of pain.

En in de bespreking van de beide gevallen merkte Cantor op: 

Effective relief of severe, persistent pain by phenytoin has been reported in cases of trigeminal neuralgia, sphenopalatine neuralgia, tabes, and peripheral neuropathy (Green, 1961; Boshes and Arieff, 1968; Meyer, et al., 1970).

Experimentally, phenytoin stabilizes electrolyte transfer across neuronal membranes and increases the neuronal threshold to repetitive stimulation. Hyperexcitability is lessened by a reduction of both post-tetanic facilitation and the duration of the after- discharge occurring after supra-threshold stimulation (Domino, 1964; Schmidt and Wilder, 1968).

Cortical responses to single repetitive thalamic stimulation are also reduced by phenytoin (Herman and Bignall, 1967). In light of these experimental results it is reasonable to postulate that phenytoin may be effective in thalamic pain by reducing the spread of abnormally excessive excitatory discharges resulting from the thalamic lesion.  

Fenytoine behoort tot de eerste generatie anti-neuropathische anti-epileptische medicatie. We neigen ertoe dit middel te vergeten, maar het kan toch vooral bij de centrale neuropathische pijn zinvol zijn. [1][2]

Werkingsmechanisme

Fenytoine stabiliseert het membraan van de zenuw, door de natriumkanalen te blokkeren. Het effect is dat zenuwen minder vaak prikkels doorgeven. Dit is juist wat beoogd wordt bij zenuwvezels (vaak C-vezels) die te gevoelig zijn geworden.[3]

Combinatie therapie: interacties

Volgens de literatuur kan fenytoine met veel andere middelen interacties geven, maar de combinatie amitriptyline-fenytoine wordt daarbij niet genoemd als problematisch.

Om dit te weten is van belang omdat bij de behandeling van neuropathische pijnen deze combinatie wel een logische combinatie is. Ook fenytoine en pregabaline (Lyrica) kan samen gegeven worden, alleen dient opgepast te worden bij al deze combi’s voor simpele farmacodynamische interacties: fenytoine, amitriptyline en pregabaline kunnen wel alle psychotrope effecten geven, bijvoorbeeld dufheid, verminderde helderheid in het hoofd, langzamer reageren, wattebollen hoofd. Bij het laag doseren van deze middelen is dat in het algemeen hoegenaamd geen issue.

In de interactiechecker op het net kunnen stoffen gevolgd worden en al hun interacties.

Ook is er geen interactie te verwachten tussen gabapentine en fenytoine, we citeren uit de VS bijsluiter:

1. Geen effecten op lever enzymen: 

Only at the highest concentration tested (171 μg/mL; 1 mM) was a slight degree of inhibition (14%-30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 μg/mL (approximately 15 times the Cmax at 3600 mg/day).Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs.

2. Geen beinvloeding van de spiegels van fenytoine: 

The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy.PhenytoinIn a single (400 mg) and multiple dose (400 mg TID) study of Neurontin in epileptic patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics. 

Nu volgt een bijzonder stuk dat we in het internet vonden. Een overzicht over fenytoine bij centrale pijn van de Dreyfus Medical Foundation:

Neuropathische pijn na beroerte (CVA) 

Drie van de vijf patienten met pijn na beroerte in het gehele aangedane gedeelte kregen 50 tot 100 mg alleen fenytoine. Allen reageerden zeer goed: geen pijn meer.[4] De twee anderen hadden een polyfarmacotherapie.

Fenytoine na infarct in thalamus

Twee patienten werden in 1972 beschreven met hevige pijnen (dysesthesieen). Beide patienten reageerden goed op fenytoine. Een patient kreeg 150 mg per dag. Wanneer fenytoine gestopt werd, kwamen de pijnen weer terug. Het weer voorschrijven van fenytoine zorgde weer voor verlichting in de pijn.[5] Bij 3 van de 8 patienten (waarvan 6 patienten een infarct van de thalamus hadden) had fenytoine een positief effect op de chronische zeer ernstige pijn.[6]

Fenytoine bij neuropathie vitamine B1 tekort

Vitamine B1 tekort kan pijnlijke neuropathie veroorzaken. Een studie heeft 12 patienten met chronische neuropathie door een vitamine B1 tekort fenytoine (100 mg per dag) of carbamazepine (200 mg per dag) gegeven. Van de 7 patienten die fenytoine kregen, moesten 2 patienten de medicatie staken vanwege lusteloosheid. Zij verwisselden fenytoine met carbamazepine. Van de 5 patienten die in het begin carbamazepine hebben gekregen, werden 2 patienten overgezet op fenytoine vanwege dezelfde bijwerking, lusteloosheid. Een patient kon geen van beide geneesmiddelen verdragen. Na 6 maanden waren de pijnscores (van 0 tot 10) duidelijk verminderd. De 7 patienten die fenytoine hebben gekregen, waren de begin en eindscores als volgt: 5-0, 6-3, 6-0, 5-1, 8-4, 8-3, en 8-4. De gemiddelde pijnscore aan het begin was 6.57 en aan het einde 2.14. Van de 4 patienten die carbamazepine hebben gekregen waren de scores: 9-1, 8-0, 8-2, en 6-4. De gemiddelde score in h
et begin was 7.75 en aan het einde een 1.75.

The authors report that their study showed carbamazepine and phenytoin to be effective (70% decrease) in relieving pain due to thiamine deficiency neuropathy.[7]

Gezichtspijn bij het Wallenbergsyndroom behandeld met fenytoine

Een patient met het syndroom van Wallenberg reageerde goed op fenytoine. Hij leed aan brandende pijn aan een kant van het gezicht rond het oog. De eerste dag kreeg hij 1000mg fenytoine verdeeld over de dag, waarna 300 mg dagelijks. In een aantal dagen verminderde de pijn duidelijk.[8]

Fenytoine contraindicaties

Bloeddyscrasieën. Acute intermitterende porfyrie. Bij parenteraal gebruik tevens: sinusbradycardie, sinoatriaal blok, tweede- en derdegraads AV-blok en adams-stokessyndroom. 

Bijwerkingen

Maag-darmklachten zoals misselijkheid, braken, obstipatie, anorexie. Centrale en andere effecten op het zenuwstelsel: duizeligheid, ataxie, nystagmus, spraakstoornissen, tremor van de handen, apathie, visusstoornissen, nervositeit, hallucinaties, neuropathie.

Verder: tandvleeshyperplasie (vooral bij kinderen) vergroving van het gelaat, vergroting van lippen, hypertrichose, allergische verschijnselen zoals artropathie, koorts, huiderupties en hepatitis, ernstige lupus erythematodes, mogelijk ook het stevens-johnsonsyndroom, lymfadenopathie in het bijzonder bij mensen met een zeer donkere huidskleur.

Ernstige leverafwijkingen, neonatale hemorragische diathese, bloeddyscrasieën (megaloblastaire anemie, trombocytopenie, leukopenie agranulocytose). Vitamine D-deficiëntie met hypocalciëmie en osteomalacie; foliumzuurdeficiëntie, remming ADH-afgifte, hyperglykemie. 

Dosering voor epilepsie: Oraal: begindosering 2–5 mg/kg lichaamsgewicht per dag en op geleide van de bloedspiegel geleidelijk (met intervallen van ten minste 7–10 dagen) aanpassen. Gebruikelijke onderhoudsdosering 200–400 mg per dag in 1 dosis.  

Bron:

Meer informatie is te vinden op Dreyfus Medical Foundation. 

Verdere informatie over Fenytoine is hieronder te vinden.

Neuropathy

3249. Wiffen, P., McQuay, H., Carroll, D., Jadad, A., and Moore, A., Anticonvulsant drugs for the management of acute and chronic pain, Cochrane Database of Systematic Reviews, 4, 1998.

3250. Sindrup, S.H. and Jensen, T.S., Pharmacologic treatment of pain in polyneuropathy, Neurology, 55(7):915-920, 2000.

3251. Ross, E.L., The evolving role of antiepileptic drugs in treating neuropathic pain, Neurology, 55(S1):S41-S46, 2000.

3252. Tanelian, D.L. and Victory, R.A., Sodium channel-blocking agents, Pain Forum, 4(2):75-80, 1995.

3253. Jensen, T.S., Anticonvulsants in neuropathic pain: Rationale and clinical evidence, Eur. J. Pain, 6:61-68, 2002.

3254. Carter, G.T. and Galer, B.S., Advances in the management of neuropathic pain, Arch. Phys.Med. Rehabil., 12(2):447-459, 2001.

3255. Tremont-Lukats, I.W., Megeff, C. and Backonja, M.M., Anticonvulsants for neuropathic pain syndromes, Drugs, 60(5):1029-52, 2000.

3256. Chojnowska, E., Which intravenous sodium channel blocker for neuropathic pain? (Letter), Anesth. Analg., 90(4):1007-1008, 2000.

3257. Belgrade, M.J. and Lev, B.I., Diabetic neuropathy – helping patients cope with their pain, Postgrad. Med., 90(5): 263-70, 1991.

3258. Thomas, P.K. and Scadding, J.W., Treatment of pain in diabetic neuropathy, Diabetic Neuropathy, 216-22, Dyck, P.J., et al, Eds., W. B. Saunders, Philadelphia, PA, 1987.

Fabry’s Disease

Lockman, Hunninghake, Krivit and DesnickNeurology (1973),1299 based on a double-blind study, report the effectiveness of PHT in the relief of the pain of Fabry’s  disease, a rare lipid storage disorder. The authors state that the single most debilitating and morbid aspect of Fabry’s disease is the pain. Excruciating crises of abdominal, chest and muscle pain, as well as arthralgias and fever, may occur episodically and last several days. A double-blind cross over study with eight patients was conducted comparing PHT with aspirin and placebo. In the comparison, relief with PHT was statistically significant (p < 0.0001). The authors note that the pain in Fabry’s disease is only partially relieved by narcotics at soporific doses.

1299. Lockman, L. A., Hunninghake, D. B., Krivit, W., and Desnick, R. J., Relief of pain of Fabry’s disease by diphenylhydantoin, Neurology, 23: 871-875, 1973.

Duperrat, Puissant, Saurat, Delanoe, Doyard and Grunfels, Annales de Dermatologie et de Syphiligraphie (1975),1813 described a twenty-three-year-old male patient who from birth had suffered from angiokeratomas and Fabry’s disease. Pain progressed in intensity over the years PHT (200 mg/day) resulted in complete disappearance of pain in less than a week. (See also Ref. 2352.)

1813. Duperrat, B., Puissant, A., Saurat, J. H., Delanoe, J., Doyard, P. A. and Grunfels, J. P., Fabry’s disease neonatal angiokeratomas. Effect of diphenylhydantoin on acute pain episodes, Ann. Derm. Syph. (Paris), 102(4): 392-3, 1975. 2352. Brady, R. O., King, F. M., Fabry’s disease, Peripheral Neuropathy, Vol. 2, Dyck, P. J., et al., Eds., W. B. Saunders Co., Philadelphia, 914-27, 1975.

Kumudchandra and Bernhard, Arthritis and Rheumatism (1979), 3259 describe a twenty-five year-old patient with confirmed Fabry disease. This patient had experienced joint pains and stiffness of shoulders, wrists, fingers and knees for six years. Salicylates and mild analgesics did not help, but codeine afforded some relief. Oral phenytoin treatment controlled the joint
pains in both the patient and his mother, who also required treatment.

3259. Kumudchandra, J.S. and Bernhard, G.C., The arthropathy of Fabry disease, Arthritis Rheum., 22(7): 781-3, 1979.

Dysesthesia (Painful Touching)

GerzPhysician’s Drug Manual (1972),1066 reports and unusual case of  “painful touching” (dysesthesia) in which a forty-year-old male patient showed dramatic response to PHT. The patient reported that a painful, intolerable, cold stream would run all over his body when touched by human hands. Because of t extreme pain on being touched, he frequently became dangerous and violent, and wanted a certificate form the clinic stating that he suffered from a “mental problem.” He was tried on a variety of medications without success. Finally he was given PHT, 100mg t.i.d. within two weeks he was completely free of disturbing symptoms.

1066. Getz, H. O., Dilantin against “painful touching” (dysthesia), Physician’s Drug Manual, 3: 144, 1972

Tabes

Dattner, in the course of a discussion of a paper by Caveness, Adams, Pope and Wegner,Transactions of the American Neurological Association (1949),48 said that some patients with lightning pains in tabes showed a favorable response to PHT or Tridione.

48. Caveness, W., Adams, R. D., Pope, A., and Wegner, W. R., The role of the dorsal root ganglia in the production of the lancinating pains of central nervous system syphilis, Trans. Amer. Neurol. Assn., 60-64, 1949.

Braham and SaiaLancet (1960),31 reported PHT effective in treating lightning pains in  two cases of tabes.

31. Braham, J. and Saia, A., Phenytoin in the treatment of trigeminal and other neuralgias, Lancet, 2: 892-893, 1960.

GreenNeurology (1961),129 reported that PHT was administered to two patients with severe lightning pains due to tabes dorsalis. Remarkable relief was obtained in both cases.

129. Green, J. B., Dilantin in the treatment of lightning pains, Neurology, 11: 257-258, 1961.

Post-Herpetic Neuralgia

ReeveLancet (1961),611 reported that PHT was effective in four cases of post-herpetic neuralgia, and recommended that a trial of PHT precede more radical treatment.

611. Reeve, H. S., Phenytoin in the treatment of trigeminal neuralgia, Lancet, 1: 404, 1961.

Hallaq and HarrisJournal of American Osteopathic Association (1969),1116 give a detailed report on the successful use of PHT in a case of post-herpetic neuralgia, with motor paralysis of an extremity, a rare complication. The patient, a seventy-six-year-old woman, had persistent pain in the right upper extremity, causing the entire limb to assume a semiflexed and adducted position. Diagnosis after examination was post-herpetic right brachial neuralgia and monoparesis. After seven days in the hospital the patient was placed on PHT, 100 mg t.i.d. Within three days she was free of pain and remained so when narcotic analgesics were with drawn and an extra 100mg of PHT was added. The patient continued free of pain as long as she to PHT.

1116. Hallaq, I. Y. and Harris, J. D., The syndrome of postherpetic neuralgia: complication and an approach to therapy, Amer. Osteopath. Assoc., 68: 1265-1267, 1969.

Thomas and MuthuswamiIndian Journal of Dermatology and Venereology (1988), 3260conducted a study to determine the usefulness of phenytoin for post-herpetic neuralgia. Thirty patients, all over 50 years old, with herpes zoster were treated with oral phenytoin 100 mg twice daily for ten days. The incidence of post-herpetic neuralgia was compared with that of post-herpetic neuralgia in another group of thirty patients treated with conventional analgesics, antacids, antihistamines and antibiotics. In the PHT-treated group, only six (20%) of the patients developed persistent neuralgia, as compared to twenty-four (80%) in the control group.

3260. Thomas, J. and Muthuswami, T.C., Diphenylhydantoin in post-herpetic neuralgia, Indian J. Dermatol. Venereol. Leprol., 54: 303-304, 1988.

See also Ref.

3261. Thomas, J. and Muthuswami, T.C., Diphenylhydantoin in post-herpetic neuralgia – A controlled study, Presented at the XVIth National Conference of Indian Association of Dermatologists, Venereologists and Leprologists, Calcutta, India, 1988.

3262. Watson, P.N. and Evans, R.J., Postherpetic neuralgia – A review, Arch. Neurol., 43:836-40, 1986.

Refractory Chronic Pain

GabkaMedizinische Monatsschrift (1963),113 reported PHT (100-300 mg/day), combined with 0.025 g of caffeine, as the most effective treatment for the relief of pain in 115 out of 142 patients.  The painful conditions included recurring headaches, migraine, genuine and symptomatic trigeminal neuralgia, post-operative jaw and facial pain, and pain following extensive facial tumor surgery. The authors state that PHT was by far the best conservative therapy in the treatment of these types of recurring head and facial pain.

113. Gabka, J., On the therapy of idiopathic and sy
mptomatic head and facial pains, Med. Mschr., 17: 430-443, 1963.

Raskin, Levinson, Pickett, Hoffman and FieldsAmerican Journal of Surgery (1974),1444 as part of a larger study, reported that two of the patients with post-sympathectomy neuralgia, unresponsive to meperidine, had immediate relief with intravenous PHT.

1444. Raskin, N. H., Levinson, S. A., Pickett, J. B., Hoffman, P. M., and Fields, H. L., Postsympathectomy neuralgia,Amer. Surg., 128: 75-78, 1974.

Taguchi, Watanabe and IokuNeurologia Medico Chirurgica (Tokyo) (1981),2998 reported a patient with bulbar syringomyelia who developed severe, intractable pain and paresthesias in her legs, abdomen and chest after cervical laminectomy. She also developed muscle spasms of her upper body. PHT, 250 mg/day, stopped both the pain and muscle spasms.

2998. Taguchi, K., Watanabe, M., Ioku, M., A case of syringomyelia: electrophysiological analysis and treatment for attacks of periodical spasms and intractable pain, Neurol. Med. Chir., 21: 135-42, 1981.

SwerdlowClinical Neuropharmalcology (1984),2997 reviewed a series of 200 patients with various types of refractory chronic lancinating or paroxysmal pain. The etiologies of the pain included post-laminectomy, post-traumatic, post-herpetic, post-operative, and post-amputation neuralgias, as well as pain secondary to nerve of plexus injury or operation, atypical facial pain, and central pain syndromes. Of fifty-two patients who received PHT as their first drug, twenty-four found it effective. This success rate was higher than that achieved with carbamazepine, clonazepam, and valproate.

2997. Swerdlow, M., Anticonvulsant drugs and chronic pain, Clin. Neuropharmacol., 7 (1): 51-82, 1984.

McCleaneAnesthesia and Analgesia (1999), 3263 reports on a randomized, double-blind, placebo-controlled, crossover study of patients suffering from neuropathic pain. Twenty patients, nine males and eleven females, with a mean age of forty years participated in the study. Patients were randomly assigned to one of two groups. Group A received an infusion of 1000 ml 0.9% saline (placebo) followed one week later by an infusion of 15 mg/kg PHT in 1000 ml 0.9% saline. Group B received the PHT infusion in week 1 and the placebo/saline infusion in week 2. Analyzed results indicated a statistically and clinically evident decrease in scores for burning pain, shooting pain, sensitivity, numbness, and overall pain with phenytoin. The authors conclude that intravenous phenytoin is a useful treatment for acute flare-ups of chronic neuropathic pain, when oral treatment is not effective or appropriate.

3263. McCleane, G.J., Intravenous infusion of phenytoin relieves neuropathic pain: a randomized, double-blind, placebo-controlled, crossover study, Anesth. Analg., 89:985-988, 1999.

See also Ref.

3264. Ashburn, M.A. and Staats, P.S., Management of chronic pain, Lancet, 353:1865-1869, 1999.

3265. France, R.D. and Krishnan, K.R., Psychotropic drugs in chronic pain, 323-74, Chronic Pain, France, R.D. and Krishnan, K.R., Eds., American Psychiatric Press, Washington, DC, 1988.

3266. Iacono, R.P., Linford, J., and Sandyk, R., Pain management after lower extremity amputation neurosurgery, Neurosurgery, 20: 496-500, 1987

.

Pain in Multiple Sclerosis

MatthewsBrain (1958),1342 reported the effectiveness of PHT in the treatment of painful spasms in a patient with multiple sclerosis. When PHT, 100 mg t.i.d., was prescribed, the attacks stopped within two days.

1342. Matthews, W. B., Tonic seizures in disseminated sclerosis, Brain, 81: 193-206, 1958.

Kuroiwa and ShibasakiFolia Psychiatrica et Neurologica Japonica (1968),1243 found that PHT and/or carbamazepine where useful in suppressing the painful tonic spasms in four patients with multiple sclerosis. In a further study, Shibaski and KuroiwaArchives of Neurology (1974),1541 reported the successful treatment of five of seven patients with PHT alone or in combination with carbanmazepine.

1243. Kuroiwa, Y. and Shibasakil H., Painful tonic seizures in multiple sclerosis-treatment with diphenylhydantoin and carbamazepine, Folia. Psychiat. Neurol. Jap., 22: 107-119, 1968.1541. Shibasaki, H. and Kuroiwa, Y., Painful tonic seizure in multiple sclerosis, Arch. Neurol., 30: 47-51, 1974.

Skillrud and GoldsteinJournal of the American Medical Association (1983),2963 reported in detail the case of a twenty-seven-year-old male physician with multiple sclerosis and paroxysmal limb hemiataxia and crossed facial paresthesias who became symptom free on 500 mg of PHT per day.

2963. Skillrud, D. M., Goldstein, N. P., Paroxysmal limb hemiataxia with crossed facial paresthesias in multiple sclerosis,JAMA, 250(20): 2843-4, 1983.

Clifford and TrotterArchives of Neurology (1984),2396 reviewing the records of 317 multiple sclerosis patients with a wide variety of painful syndromes and therapies, reported PHT’s usefulness in the treatment of limb, facial, head and thoracic pain.

2396. Clifford, D. B., Trotter, J. L., Pain in multiple sclerosis, Arch. Neurol., 41: 1270-2, 1984.

style="font-size: 10pt; font-family: Arial, Helvetica, sans-serif">Reflex Sympathetic Dystrophy

ChaturvediPain (1989), 3267 describes the use of phenytoin to treat a thirty-year-old patient who had been complaining of pain in the left lower limb for two years. The symptoms had begun six months after a bicycle fall. The pain (a burning of moderate intensity) started gradually in the left lower limb and over time involved the entire leg to about 3 in. above the knee. Emotional reactions, touch, and heat all increased the pain. He had been seen by several physicians, surgeons, orthopedists and physiotherapists in the past, but had not experienced any relief. Therapies tried unsuccessfully effects included: several analgesics; vitamin injections and tablets; minor tranquillizers; and tricyclic antidepressants, alone or in combination; as well as vitamin B (B1, B6, B12) given for two months without any relief. After receiving phenytoin (100 mg b.i.d) for two weeks, the patient reported a slight amelioration of his pain (20%). The dose of phenytoin was increased to 300 mg (100 mg t.i.d) and, after one month, the patient reported that he had more than 50% pain relief and was able to do his work effectively. When PHT was not taken for two weeks, the patient’s symptoms worsened. On resuming PHT again, his symptoms promptly decreased. After one year of treatment, phenytoin was tapered and stopped. The patient continued to have good pain relief (75-80%).

3267. Chaturvedi, S.K., Phenytoin in reflex sympathetic dystrophy, Pain, 36: 379-380, 1989.

Koman, Barden, Smith, Pollock, Sinai and PoehlingFoot and Ankle (1993), 3268 present the case history of a patient with reflex sympathetic dystrophy of the foot. The patient, a 12-year-old girl, had injured her left foot on a lawn mower. Despite the use of analgesics, elevation, rest, crutches and protective splinting, she experienced increasing pain, cold intolerance, stiffness, and disability. Burning dysesthesia disrupted her sleep. Her foot was anhidrotic, swollen, dysesthetic and allodynic. The patient was admitted to the hospital and started on a regimen of amitriptyline (25 mg po, t.i.d), phenytoin (100 mg po t.i.d), and physical therapy with stress loading. Five days later, comparison of earlier results of the thermoregulatory and vasomotor capacity tests showed less vasomotor instability and more appropriate thermoregulatory responses. In two weeks, the patient had returned to school. At this point, she was significantly improved and fully weight bearing, although she still experienced mild allodynia (pain resulting from non-noxious stimuli to normal skin). Phenytoin was discontinued and the amitriptyline was tapered. When seen two months later, the patient had continued to improve, was taking no medications, and had normal vasomotor stability and thermoregulatory responses.

3268. Koman, L.A., Barden, A., Smith, B.P., Pollock, F.E., Sinai, S., and Poehling, G.G., Reflex sympathetic dystrophy in an adolescent, Foot and Ankle, 14(5): 273-77, 1993.

Abdominal Pain

Kellaway, Crawley and KagawaEpilepsia (1959-1960),551 in a review of experience with a group of 459 children who had consistent 14- and 6-per-second spike patterns on the EEG and whose primary complaints were headache and abdominal pain, found the most effective treatments were PHT and Diamoc, alone or in combination.

551. Kellaway, P.,Crawley,I.W.,and Kagawa, N., Paroxysmal pain and autonomic disturbances of cerebral origin: a specific electro-clinical syndrome, Epilepsia, 1: 466-483, 1959-1960.

Peppercorn, Herzog, Sichter and MaymanJAMA (1978),2018 found PHT useful in the treatment of three patients with paroxysmal abdominal pain. When two of the patients stopped their medication the symptoms returned. With the resumption of the medication symptoms disappeared.

2018. Peppercorn, M. A., Herzog, A. G., Dichter, M. A. and Mayman, C. I., Abdominal epilepsy-a cause of abdominal pain in adults, JAMA, 240(22): 2450-51, 1978.

Schafler and KarbowskiSchweizerische Medizinische Wochenschrift (1981),2928 reported six cases of paroxysmal abdominal pain occurring in association with cerebral dysrhythmias, PHT controlled or reduced the severity of the attacks in the four cases in which it was used alone. In the one case, PHT, in combination with carbamazepine, was used successfully and, in another case, carbamaxepine was used alone.

2928. Schaffler, L., Karbowski, K., Relapsing paroxysmal abdominal pains of cerebral origin, Schweiz. Med. Wochenschr., 111(37): 2352-60, 1981.

Analgesia: General

Webb and KamaliPain, (1998), 3679 evaluated the analgesic effects of single doses of phenytoin (300 mg), lamotrigine (300 mg), and dihydrocodeine (90 mg) (each given on four occasions) in a double-blind, randomized, placebo-controlled crossover study in twelve non-smoking volunteers (age 20-26). A computerized cold-pressor test (CPT) was used to measure analgesia levels. Psychomotor tests were carried out before each CPT to assess possible drug-induced sedation. Subjective assessments of concentration, vigilance, and relaxation were also measured using visual analog scales. Maximum pain relief was achieved at 1.25 hours post-dose for both lamotrigine and dihydrocodeine, whereas the maximum analgesic effect of PHT occurred at 4.25 hours. There was a significant association between analgesia and plasma concentrations of both lamotrigine and phenytoin. Sedation was not seen with any of the drugs, compared to placebo. The authors suggest that both phenytoin and lamotrigine could have wider use as analgesics.

3679. Webb, J. and, Kamali, F., Analgesic effects of lamotrigine and phenytoin on cold-induced pain: a crossover placebo-controlled study in healthy volunteers, Pain, 76: 357-363, 1998.

Cancer Pain

Shah and SharmaPain (1990), 3270 investigated the effects o
f phenytoin for pain relief in patients with head and neck cancer. Sixty patients received 100 mg PHT 3 to 4 times a day and pain relief was evaluated by scoring good relief (greater than 60%), fair (30-59%), and poor (less than 30%). Phenytoin produced good pain relief, especially shooting pain, in 37.1% of the patients and fair relief in 42. 9%. Duration of pain relief was approximately 3 to 4 hours. The authors also noted PHT’s usefulness in reducing hyperesthesia over post surgical scars.

3270. Shah, S. and Sharma, K., Use of phenytoin in head and neck cancer pain, Sixth World Congress on Pain, Adelaide, Australia, 1-6, April 1990, Pain, Suppl 5: S357, 1990.

BhatiaAntiseptic (1991), 3271 assessed the effect of oral phenytoin (200-400 mg/day) on pain relief in fifty patients with proven malignancy of the head and neck. Phenytoin was beneficial in forty-five (90%) of the patients. Improvements in mood, pain tolerance and analgesic efficacy, particularly in spasmodic and throbbing pain, were remarkable. No additional anti-pain therapy was required for these terminal cancer patients from a remote, rural area of India. No adverse effects were noted. The author concludes that symptom control with PHT alone in terminal cancer patients having mild to moderate pain can be sufficient. Narcotic drugs may not be required. Importantly, as the author points out, phenytoin is safe, inexpensive and available.

3271. Bhatia, M.T., Simplified approach for relief of terminal cancer pain with phenytoin sodium, Antiseptic, 88(1): 18-22, 1991.

BhatiaJournal of the Indian Medical Association (1991), 3272 studied the analgesic efficacy of 200-400 mg phenytoin as a sole treatment for the control of pain in cancer patients in rural India. Of the total of eighty patients, thirty-nine had carcinoma of the cervix; seventeen, breast carcinoma; and twenty-four, cancer of the head and neck. Patients experienced spasmodic throbbing, burning, sharp or cutting type pain that was assessed by an objective numerical questionnaire. Phenytoin relieved 80% of the pain and related symptoms in thirty-eight patients (47%). Twenty-three patients (29%) had pain and symptom control between 60-80%. Thirteen patients (16%) had symptom control between 40-60%. Phenytoin also improved mood and sense of well-being in seventy-two of the eighty patients.

3272. Bhatia, M.T., Anticonvulsant alone in the relief of cancer pain, J. Indian Med. Assoc., 90(11): 301-2, 1992.

BhatiaPersonal Communication (1992), 3273 presents, in tabular form, data on 30 patients treated with combined aspirin and Dilantin for terminal cancer pain. For each patient, the sex, age, type of cancer, and individual dosage and frequency of administration of aspirin and Dilantin are listed. The relief of pain, provided by the combined therapy, for each cancer patient is given.

3273. Bhatia, M.T., Combination of dilantin with aspirin in relief of terminal cancer pain, Personal Communication, 1-3, 1992.

Yajnik, Singh, Singh and KumarJournal of Pain and Symptom Management (1992), 3274evaluated the efficacy of phenytoin (PHT), buprenorphine (Bu), and Bu + PHT for the relief of cancer pain of various etiologies. A randomized, double-blind one-month study of three groups, each comprised of twenty-five patients, was conducted. PHT (100 mg po twice daily) provided > 50% pain relief to eighteen patients (72%) and > 75% relief to four patients (16%). Bu (0.2 mg sublingually twice daily) gave twenty-one patients (84%) > 50% relief, and fifteen patients (60%) > 75% relief. Eight Bu-treated patients had serious side effects, while none of the phenytoin-treated patients experienced problems. Combined therapy (PHT, 50 mg po + Bu 0.2 mg SL twice daily) provided > 50% pain relief to twenty-two patients (88%) and > 75% to eighteen (72%). Only one patient experienced a serious side effect. This study suggests that phenytoin has mild to moderate pain relieving properties of its own and can significantly enhance buprenorphine analgesia. The authors state that further clinical trials of PHT in the relief of cancer pain are warranted.

3274. Yajnik, S., Singh, G.P., Singh, G., and Kumar, M., Phenytoin as co-analgesic in cancer pain, J. Pain Symp. Manage., 7(4): 209-213, 1992.

ChangJournal of Pain and Symptom Management (1997), 3275 report the use of intravenous and oral phenytoin to control rapidly progressive severe pelvic and lower extremity pain in a 58-year-old woman with metastatic fibrosarcoma. Morphine alone,(10 mg/hr or 120 mg every 4 hours, up to 540 mg/day), intravenous and oral, failed to relieve the pain or produced unacceptable side effects. A 500 mg loading dose of intravenous phenytoin produced near complete relief of her pain within an hour. She was discharged on phenytoin (199 mg twice a day), desipramine (25 mg daily), lorazepam (0.5 mg twice a day), and morphine (120 mg every 4 hr) with good pain control. Cessation of the phenytoin led to pain recurrence and so the phenytoin was continued for 9 mos, until her death.

3275. Chang, V.T., Intravenous phenytoin in the management of crescendo pelvic cancer-related pain, J. Pain Symp. Manage., 13(4):238-240, 1997.

See also Ref.

3276. Portenoy, R.K. and Lesage, P., Management of cancer pain, Lancet, 353:1695-1700, 1999.

Other clinical reviews and studies on the use of PHT in pain: facial pain including trigeminal neuralgia, glossopharyngeal neuralgia, and temporomandibular joint syndrome, Refs. 2470, 2472, 2492, 2523, 2593, 2619, 2801, 2847, 2943; headache including migraine, Refs. 2317, 2492; post-herpetic neuralgia, Ref. 2474, 2657; reflex sympathetic systrophy and post-sympathectomy pain, Refs. 2492, 3040; pain in multiple sclerosis Refs. 2601, 2929; central and other chronic pain syndromes, Refs. 2452, 2460, 2492, 2756, 2784, 2997.

2470. Dworkin, S. F., Benign chronic orofacial pain. Clinical criteria and therapeutic approaches, Postgrad. Med., 74(3): 239-48, 1983.
2472. Editor, Management of trigeminal neuralgia, Lancet, 662-3, Mar 24, 1984.
2492. Fields, H. L., Raskin, N. H., Anticonvulsants and pain, Clinical Neuropharmacology, Klawans, H. L., Ed., Raven Press, New York, 173-83, 1976.
2523. Gangarosa, L. P., Mahan, P. E., Pharmacologic management of TMJ-MPDS, Ear Nose Throat J., 61: 670-8, 1982.
2593. Hier, D. B., Headache, Manual of Neurologic Therapeutics, 2nd Edition, Samuels, M. A., Ed., Little, Brown & Co., Boston, 15-29, 1982.
2619. Jannetta, P. J., Medical treatment of trigeminal neuralgia, Neurological Surgery of the Ear and Skull Base, Brackmann, D. E., Ed., Raven Press, New York, 145-8, 1982.
2801. Mohr, J. P., Facial pain, Manual of Clinical Problems in Neurology, Little, Brown and Co., Boston, 97-8, 1984.
2847. Pagni, C. A., Trigeminal neuralgia, Panminerva Med., 24: 113-36, 1982.
2943. Selby, G., Diseases of the fifth cranial nerve, Peripheral Neuropathy, Vol. 1, Dyck, P. J., et al., Eds., W. B. Saunders Co., Philadelphia, 533-69, 1975.
2317. Behan, P., Migraine: a rational approach to therapy, Br. J. Clin. Pract., 36(10): 359-62, 1982.
2474. Edwards, W. T., Approaches to managing chronic pain, Med. Times, 110: 3s-11s, 1982.
2657. Kepes, E. R., Management of pain, Fundamentals of Geriatric medicine, Cape, R. D., et al., Eds., Raven Press, New York, 247-57, 1983.
3040. Urbaniak, J. R., Roth, J. H., Office diagnosis and treatment of hand pain, Orthop. Clin. North Am., 13: 477-95, 1982.
2601. Holland, N. J., Wiesel-Levison, P., McDonnel, M., Nursing care, Multiple Sclerosis, A Guide for Patients and Their Families, Scheinberg, L. C., Ed., Raven Press, New York, 111-28, 1984.
2929. Scheinberg, L., Giesser, B. S., Drug therapy, Multiple Sclerosis a Guide for Patients and Their Families, Scheinberg, L., Ed., Raven Press, New York, 45-55, 1984.
2452. Digregorio, G. J., Barbieri, E. J., Pharmacologic management of pain, Am. Fam. Physician, 27: 185-8, 1983.
2460. Dougherty, R. J., Office management of chronic pain, Postgrad. Med., 76(2): 215-18, 1984.
2756. Maciewicz, R., Bouckoms, A., Martin, J. B., Drug therapy of neuropathic pain, Clin. J. Pain, l(l): 1-10, 1985.
2784. Mehta, M., Chronic pain, Recent Advances in Anaesthesia and Analgesia, Atkinson, R. S. and Hewer, L. C., Eds., Churchill Livingstone, New York, 157-77, 1982.
2997. Swerdlow, M., Anticonvulsant drugs and chronic pain, Clin. Neuropharmacol., 7 (1): 51-82, 1984.

 

Auteurs: Prof.dr. Jan M. Keppel Hesselink, MD, PhD en Drs David J. Kopsky, MD, versie januari 2009   

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