title: Morphine and clonidine combination therapy improves therapeutic window in mice: synergy in antinociceptive but not in sedative or cardiovascular effects.
abstract: Opioids are used to manage all types of pain including acute, cancer, chronic neuropathic and inflammatory pain. Unfortunately, opioid-related adverse effects such as respiratory depression, tolerance, physical dependence and addiction have led to an underutilization of these compounds for adequate pain relief. One strategy to improve the therapeutic utility of opioids is to co-administer them with other analgesic agents such as agonists acting at α2-adrenergic receptors (α2ARs). Analgesics acting at α2ARs and opioid receptors (ORs) frequently synergize when co-administered in vivo. Multimodal analgesic techniques offer advantages over single drug treatments as synergistic combination therapies produce analgesia at lower doses, thus reducing undesired side effects. This inference presumes, however, that the synergistic interaction is limited to the analgesic effects. In order to test this hypothesis, we examined the effects of α2AR/OR combination therapy in acute antinociception and in the often-undesired side effects of sedation and cardiovascular depression in awake unrestrained mice. Morphine, clonidine or their combination was administered by spinal or systemic injection in awake mice. Antinociception was determined using the warm water tail flick assay (52.5°C). Sedation/motor impairment was evaluated using the accelerating rotarod assay and cardiovascular function was monitored by pulse oximetry. Data were converted to percent maximum possible effect and isobolographic analysis was performed to determine if an interaction was subadditive, additive or synergistic. Synergistic interactions between morphine and clonidine were observed in the antinociceptive but not in the sedative/motor or cardiovascular effects. As a result, the therapeutic window was improved ∼200-fold and antinociception was achieved at non-sedating doses with little to no cardiovascular depression. In addition, combination therapy resulted in greater maximum analgesic efficacy over either drug alone. These data support the utility of combination adrenergic/opioid therapy in pain management for antinociceptive efficacy with reduced side-effect liability.
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec, Canada; Department of Anesthesiology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Stone
authors.affiliation: Department of Neuroscience, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: German
authors.affiliation: Department of Neuroscience, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Kelly F
authors.initials: KF
authors.lastname: Kitto
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Neuroscience, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Fairbanks
authors.affiliation: Department of Neuroscience, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Dermatology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: George L
authors.initials: GL
authors.lastname: Wilcox
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000473:pathology; D003000:Clonidine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage; D007278:Injections, Spinal; D051379:Mice; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism
chemical_list: D000700:Analgesics; D006993:Hypnotics and Sedatives; D018341:Receptors, Adrenergic, alpha-2; D011957:Receptors, Opioid; D009020:Morphine; D003000:Clonidine