Effect of the combined use of tramadol and milnacipran on pain threshold in an animal model of fibromyalgia.
OBJECTIVE
Acidic saline injections produce mechanical hyperresponsiveness in male Sprague-Dawley rats. We investigated the effect of milnacipran in conjunction with tramadol on the pain threshold in an acidic saline animal model of pain.


METHODS
The left gastrocnemius muscle of 20 male rats was injected with 100 microL of saline at pH 4.0 under brief isoflurane anesthesia on days 0 and 5. Rats administered acidic saline injections were separated into four study subgroups. After determining the pre-drug pain threshold, rats were injected intraperitoneally with one of the following regimens; saline, milnacipran alone (60 mg/kg), milnacipran (40 mg/kg) plus tramadol (20 mg/kg), or milnacipran (40 mg/kg) plus tramadol (40 mg/kg). Paw withdrawal in response to pressure was measured at 30 min, 120 min, and 5 days after injection. Nociceptive thresholds, expressed in grams, were measured with a Dynamic Plantar Aesthesiometer (Ugo Basile, Italy) by applying increasing pressure to the right or left hind paw until the rat withdrew the paw.


RESULTS
A potent antihyperalgesic effect was observed when tramadol and milnacipran were used in combination (injected paw, p=0.001; contralateral paw, p=0.012). This finding was observed only at 30 min after the combination treatment.


CONCLUSIONS
We observed potentiation of the antihyperalgesic effect when milnacipran and tramadol were administered in combination in an animal model of fibromyalgia. Further research is required to determine the efficacy of various combination treatments in fibromyalgia in humans.
Kim
Seong-Ho
SH
Department of Internal Medicine, Dongguk University College of Medicine, Gyeongju, Korea. junjan@dongguk.ac.kr
Song
Junhwa
J
Mun
Hyunil
H
Park
Keon Uk
KU
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005356:Fibromyalgia / Q000139:chemically induced / Q000150:complications / Q000517:prevention & control*; D006863:Hydrogen-Ion Concentration; D006930:Hyperalgesia / Q000209:etiology / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D008297:Male; D000078764:Milnacipran; D010146:Pain / Q000209:etiology / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D013997:Time Factors; D014147:Tramadol / Q000008:administration & dosage / Q000494:pharmacology*
D000701:Analgesics, Opioid; D000928:Antidepressive Agents; D003521:Cyclopropanes; D014147:Tramadol; D012965:Sodium Chloride; D000078764:Milnacipran