Effect of the Combined Use of Tramadol and Milnacipran on Pain Threshold in an Animal Model of Fibromyalgia

Abstract

Background/AimsAcidic 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.MethodsThe left gastrocnemius muscle of 20 male rats was injected with 100 µL 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.ResultsA 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.ConclusionsWe 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.

Neurobiology of fibromyalgia and chronic widespread pain

“…while the hypersensitivity once developed is reversed by blockade of excitatory activity spinally or supraspinally (Skyba et al, 2002, Hoeger-Bement and Sluka, 2003, Tillu et al, 2008, da Silva et al, 2010a, da Silva et al, 2010b). Further the non-inflammatory pain model shows a similar pharmacological management profile to clinical treatment of fibromyalgia: reductions in pain and hyperalgesia by antidepressants, anticonvulsants, opioids, glutamate receptor antagonists, K + channel openers, Na+ channel blocker and exercise, but not NSAIDS (Sluka et al, 2002, Nielsen et al, 2004, Bement and Sluka, 2005, Miranda et al, 2006, Yokoyama et al, 2007a, Kim et al, 2009, Sharma et al, 2010). Thus, the non-inflammatory pain models mimic the clinical presentation of signs and symptoms observed in fibromyalgia with widespread hyperalgesia, minimal muscle tissue damage, alterations in central nociceptive processing, greater hyperalgesia in females, and are responsive to the same pharmacological and non-pharmacological therapies.…”

Analgesic efficacy of CR4056, a novel imidazoline-2 receptor ligand, in rat models of inflammatory and neuropathic pain

“…Ipsilateral and contralateral paw withdrawal thresholds were measured in response to mechanical stimuli on days 0 (baseline – 0d), 5 (5d) and 24 hours after the second acid injection (6d). Nociceptive thresholds, expressed in grams (g), were measured using a Dynamic Plantar Aesthesiometer (Ugo Basile, Comerio Varese, Italy) by applying increasing pressure to the right and left hind paw until the rat withdrew the paw 23. A maximal cut-off of 50 g was used to prevent tissue damage.…”

Animal models of fibromyalgia

“…Pregabalin (anticonvulsant drug) decreases both cutaneous and deep tissue hyperalgesia (male rats) [ 25 ]. Moreover, tramadol (a centrally acting synthetic opioid analgesic used to treat moderate to moderately severe pain) and milnacipran (a serotonin-norepinephrine reuptake inhibitor used in the clinical treatment of FMS) showed a potent antihyperalgesic effect when administered together (male rats) [ 27 ]. Taken together, acid-induced hyperalgesia is able to be reversed by a series of analgesic strategies commonly used clinically in FMS.…”