title: Evidence from basic research for opioid combinations.
abstract: BACKGROUND
  Single opioid analgesics are modestly effective in reducing pain but have a narrow therapeutic index and frequently produce intolerable side effects. Adjuvant analgesics are often used to improve the opioid therapeutic index. Basic science research has accumulated evidence that opioid combinations in animal models and in vitro have potential to improve the therapeutic index of opioids and/or prevent opioid tolerance.
  
  
  METHODS
  Opioid receptor pharmacology is reviewed including receptor genetics and downstream signaling. Receptor functional selectivity and ligand biased responses are discussed in relationship to opioid pharmacodynamics, signal modulation and synergy. The accumulated bench research over the past decade, in particular, provides a rationale for considering clinical trials of opioid combinations. These combinations include both selective agonist-agonist or agonist-antagonist pairs which are reviewed.
  
  
  CONCLUSIONS
  The use of opioid antagonists (naloxone and naltrexone), oxycodone, fentanyl and methadone with morphine improves analgesia in animal models and blunts physical dependence and conditioned place preference (a marker for psychological dependence). Sequential or simultaneous dosing schedules, dose levels or ratios need to be explored further. Pain phenotype may be an important factor predicting responses to combinations such that trial design will need to take this into account. Side effects will need to be monitored closely as little is known about the influence of opioid combinations on side effects.
authors.affiliation: Taussig Cancer Institute, Case Western Reserve University, Lerner School of Medicine, Cleveland Clinic, Palliative Medicine and Supportive Oncology Services, Cleveland, OH 44195, USA. davism6@ccf.org
authors.forename: Mellar P
authors.initials: MP
authors.lastname: Davis
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D006801:Humans; D008024:Ligands; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000517:prevention & control; D010146:Pain / Q000188:drug therapy*; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D009292:Narcotic Antagonists; D011957:Receptors, Opioid