title: Opioids: a two-faced Janus.
abstract: BACKGROUND
  Long-term pain is a debilitating condition that is costly to treat and has a significant impact on patient quality of life. Classical opioids have been used for the treatment of pain for centuries and are one of the most effective drug classes available for acute severe pain and long-term pain. However, concerns regarding adverse effects, tolerance to analgesic effects and the potential for addiction have resulted in a reluctance to prescribe and use opioids for the management of long-term non-cancer pain. Adverse events, including gastrointestinal side effects such as constipation, nausea and vomiting, and central nervous system side effects such as sedation are responsible for as many as one in five patients discontinuing opioid treatment, often leading to inadequate pain relief and poor patient quality of life. Therefore, new analgesic therapies are needed that are associated with fewer adverse effects, whilst providing sustainable pain relief for patients with long-term pain.
  
  
  OBJECTIVE
  To provide an overview of the historical development, uses, mechanisms of action, receptor affinities and side-effect profiles of classical opioids. In addition, recent developments and novel approaches for long-term, severe pain treatment are also reviewed.
  
  
  RESULTS
  A number of treatment strategies were identified: co-administration with opioid-sparing analgesics to reduce side effects and/or risk of dependence, the use of peripheral opioid antagonists and novel delivery mechanisms to reduce side effects, the development of non-opioid agents that reduce side effects and enhance analgesia such as glial cell modulators, and the development of novel agents with combined µ-receptor and monoaminergic activity within the same molecule.
  
  
  CONCLUSIONS
  Despite these recent advances, there have been very few completely novel drug developments. Hence, there remains a continuing need for innovative therapeutic strategies for the treatment of long-term pain. The most promising alternatives appear to be the use of traditional opioids together with peripheral opioid antagonists, combining opioids with glial cell modulators, and the use of novel agents with µ-receptor agonist and noradrenaline reuptake inhibitor activity within the same molecule (MOR-NRI compounds).
authors.affiliation: Department of Anesthesiology, Surgical Services and Intensive Care, Karolinska University Hospital, Stockholm, Sweden. karsten@narkos.se
authors.forename: Karsten
authors.initials: K
authors.lastname: Ahlbeck
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects* / Q000138:chemical synthesis / Q000627:therapeutic use*; D000818:Animals; D004338:Drug Combinations; D016503:Drug Delivery Systems / Q000379:methods / Q000639:trends; D055808:Drug Discovery; D006801:Humans; D009293:Opioid-Related Disorders / Q000453:epidemiology / Q000517:prevention & control; D010146:Pain / Q000188:drug therapy*; D012720:Severity of Illness Index
chemical_list: D000701:Analgesics, Opioid; D004338:Drug Combinations