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THE synthetic analogue of methionine enkephalin, FK 33-824, exerts a long-lasting and potent analgesic effect in animals after systemic and enteral administration. In high doses it produces tolerance, cross-tolerance with morphine, and dependence in monkeys. Like β-endorphin, FK 33-824 produces akinaesia in rats and rabbits. All effects seen in animals can be abolished by naloxone. We report here on the results of the first studies performed with FK 33-824 in man (tolerance, electroencephalogram (EEG), endocrine profile and plasma levels), as a basis for future therapeutic studies.
Eight psychiatric patients with tardive dyskinesia (TD) were treated with single doses of the synthetic met-enkephalin analogue FK 33-824 (1, 2, and 3 mg IM) morphine (10 mg SC) and naloxone, an opiate receptor antagonist (0.8 mg IM). The drug effects were assessed by blind evaluation of randomly sequenced videotapes made before and during treatment. FK 33-824 (1, 2, and 3 mg IM) slightly reduced TD (P < 0.05) and increased preexisting bradykinesia. The effect on TD, however, was pronounced only in patients concurrently treated with neuroleptics in relatively high doses. Morphine had a similar although weaker antihyperkinetic effect, whereas naloxone had no effect. Side effects of FK 33-824 included dizziness, heaviness in the extremities, slurred speech, and dryness of mouth. Morphine caused drowsiness, dizziness, ataxia, and nausea, and naloxone had no side effects. The results do not point to a primary role of enkephalin in the pathophysiology of TD, but enkephalin may interact with dopamine functions and potentiate some of the effects of neuroleptic drugs.
Bjørndal, N., Casey, D. E., & Gerlach, J. (1980). Enkephalin, morphine, and naloxone in tardive dyskinesia. Psychopharmacology, 69(2), 133-136.
Natural enkephalins exert weak and transitory analgesic effects. The synthetic enkephalin, FK 33-824 (FK), is less susceptible to metabolic breakdown and produces long-lasting analgesia in animals. The present studies examined the effects of FK on threshold and tolerance of electrically evoked pain in man under double blind conditions. 1.0 mg FK given intramuscularly (saline control) increased tolerance significantly without affecting the pain threshold, but also produced vasodilatation and feelings of oppression and heaviness (study I). In study II, where 50 mg betazole was employed as "placebo" because of its vasodilatatory effects, 1.0 mg FK increased pain tolerance significantly more than 0.25 mg FK while the threshold remained unchanged. Self-ratings of activation and well-being decreased; those of oppression increased, as did reaction time, equally after 0.25 and 1.0 mg FK but were not altered by betazole. In conclusion, 1.0 mg FK i.m. increases tolerance but not perception of pain, thus mimicking the analgesic effects of morphine.
Stacher, G., Bauer, P., Steinringer, H., Schreiber, E., & Schmierer, G. (1979). Effects of the synthetic enkephalin analogue FK 33-824 on pain threshold and pain tolerance in man. Pain, 7(2), 159-172.