Topical methadone and meperidine analgesic synergy in the mouse.

Topical analgesics have many potential advantages over systemic administration. Prior work has shown potent analgesic activity of a number of topical opioids in the radiant heat tail-flick assay. The current study confirms the analgesic activity of morphine and extends it to two other mu opioids, methadone and meperidine. Combinations of topical morphine and lidocaine are synergistic. Similarly, the combination of methadone and lidocaine is synergistic. While there appeared to be some potentiation with the combination of meperidine and lidocaine, it did not achieve significance. Systemically, prior studies have shown that co-administration of morphine and methadone was synergistic. The combination of morphine and methadone was also synergistic when given topically. In contrast, the combination of morphine and meperidine was not synergistic systemically and it was not synergistic topically. Thus, the pharmacology of topical opioids mimics that seen with systemic administration. Their activity in the topical model supports their potential utility while the local limitation of their actions offers the possibility of a reduced side-effect profile.

Opposing actions of neuronal nitric oxide synthase isoforms in formalin-induced pain in mice.

The role of central and peripheral neuronal nitric oxide synthase (nNOS) splice variants in the development of inflammatory hyperalgesia was investigated using the formalin test. Supraspinal administration of the NOS inhibitor NOArg lowered both the first and second phase of the formalin response. An oligodeoxynucleotide targeting four nNOS isoforms given supraspinally also reduced the formalin response of both phases. Supraspinal antisense mapping suggested that this effect results from the nNOS-1 splice variant, implying that nNOS-1 is important in mediating formalin pain. At the spinal level, antisense mapping suggested a role of both the nNOS-1 and the nNOS-beta variants in producing formalin pain. Conversely, an antisense selective against nNOS-2 had an opposing effect against the first phase, increasing its intensity. This result, which was similar to prior studies examining opioid actions, implies that endogenous nNOS-2 activity acted to minimize pain perception. Locally in the foot, arginine, the precursor for NO, increased the phase II response at low doses while higher doses reduced the response. This complex biphasic response suggested opposing NOS actions. Local antisense mapping again showed that nNOS-1 is involved in producing phase II of the formalin response while nNOS-2 had an opposite effect similar to that seen spinally. Finally, downregulation of nNOS-1 by antisense prevented tolerance to morphine in both the tail-flick and the formalin test. Together, these observations illustrate the complexity of nNOS in pain perception and the existence of opposing nNOS systems likely due to splice variants of nNOS.

The synergistic analgesic interactions between hydrocodone and ibuprofen.

UNLABELLED: The practice of combining opioids with nonsteroidal antiinflammatory drugs is widespread in the clinical management of acute and chronic pain. Using the mouse radiant heat tail-flick nociception model, we observed potent analgesia with hydrocodone. In contrast, ibuprofen as a single drug was inactive in this model of moderate to severe pain, perhaps reflecting its limited analgesic potential. Despite the inactivity of ibuprofen alone in this model, the inclusion of ibuprofen with hydrocodone markedly enhanced the analgesic response. Dose-response studies revealed an 50% effective dose for hydrocodone alone in mice of 11 mg/kg, SC. Inclusion of a fixed ibuprofen dose with the various hydrocodone doses shifted the 50% effective dose value almost seven-fold to the left to 1.6 mg/kg, SC, despite the lack of effect of ibuprofen alone in this model. Using a fixed hydrocodone:ibuprofen ratio (1:40) also revealed a marked four-fold shift to 2.6 mg/kg, SC. These findings suggest a synergistic interaction between ibuprofen and hydrocodone in a noninflammatory pain model. IMPLICATIONS: Opioids are frequently used in combination with nonsteroidal antiinflammatory drugs clinically. These studies demonstrate strong interactions between ibuprofen and hydrocodone, implying synergy between the two drugs, which may help explain their utility when given together.

Analgesic synergy between topical morphine and butamben in mice.

UNLABELLED: Studies have revealed that lidocaine is an effective analgesic when applied topically to the tail of a mouse in the radiant heat tail-flick assay. In addition, the topical combination of lidocaine with morphine revealed synergistic interactions between the two drugs. In the current studies, we demonstrate that topical butamben, benzocaine, and bupivacaine are active in the radiant heat tail-flick assay. In this assay, topical lidocaine has a ceiling effect and displays a biphasic curve, with large doses markedly decreasing the responses almost to baseline levels. In contrast, butamben has an S-shape dose-dependent response in the assay and did not display a biphasic curve as seen with lidocaine, suggesting that topical butamben may have advantages over lidocaine. Both benzocaine and bupivacaine also showed dose-dependent analgesic activity in this model. Like lidocaine, butamben/morphine combinations displayed synergistic interactions. Indeed, the synergy appeared more prominent with a butamben/morphine combination. We also observed synergy between topical benzocaine and morphine. Although the bupivacaine/morphine combination was suggestive of synergy on isobolographic analysis, it did not achieve statistical significance. These studies indicate that a series of local anesthetics are all active topically in the radiant heat tail-flick assay in mice and that several interact synergistically with morphine. Of the local anesthetics tested, butamben seemed to have several pharmacological characteristics, alone and in combination with morphine, which suggest that it may be superior to the other local anesthetics. Together, these observations suggest that topical combinations of opioids and local anesthetics may prove clinically valuable. IMPLICATIONS: Topical administration of the opioid micro -agonist morphine and the sodium channel inhibitors butamben and benzocaine results in a synergistic interaction for antinociception in radiant heat tail-flick assay in mice, suggesting that the combination of these drugs will enhance rather than detract from the analgesia of either alone.

The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids.

Once daily s.c. administration of 5 mg/kg morphine, a mu-opioid agonist, or U50488H (U50), a kappa 1-opioid agonist, for 5 days in male CD-1 mice results in a 2-3-fold shift to the right of the respective analgesic (tail flick) dose-response curves, indicating the development of tolerance. Concurrent s.c. administration of the competitive NMDA receptor antagonist, LY274614 (LY), at 24 mg/kg/24 h infusion (osmotic pump) or 6 mg/kg i.p. once daily attenuates the development of morphine tolerance, when the response to saline plus morphine is compared on day 5 with LY plus morphine. Using this paradigm, once daily administration of either the non-competitive NMDA antagonist, MK-801, at 0.3 mg/kg i.p. or the nitric oxide synthase inhibitor, NG-nitro-L-arginine (NorArg), at 1 mg/kg i.p. twice daily attenuated the development of morphine tolerance. None of these drugs modify the tail-flick response or alter the ED50 for morphine. In contrast, co-administration of LY, MK-801 or NorArg, as above, failed to attenuate the development of tolerance to U50 or to the kappa 3-opioid agonist, naloxone benzoylhydrazone (NalBzoH). These results suggest that mu-opioid tolerance but not kappa 1- or kappa 3-opioid tolerance involves the mediation of NMDA receptors and the nitric oxide system.