New concepts in opioid analgesia

ABSTRACT

Introduction: Opioids are the oldest and most potent drugs for the treatment of severe pain, but they are burdened by detrimental side effects such as respiratory depression, addiction, sedation, nausea, and constipation. Their clinical application is undisputed in acute (e.g. perioperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny and has contributed to the current ‘opioid crisis.’

Areas covered: This article reviews pharmacological principles and research strategies aiming at novel opioids with reduced side effects. Basic mechanisms underlying pain, opioid analgesia, and other opioid actions are outlined. To illustrate the clinical situation and medical needs, plasticity of opioid receptors, intracellular signaling pathways, endogenous and exogenous opioid receptor ligands, central and peripheral sites of analgesic, and side effects are discussed.

Expert opinion: The epidemic of opioid misuse has taught us that there is a lack of fundamental knowledge about the characteristics and management of chronic pain, that conflicts of interest and validity of models must be considered in the context of drug development, and that novel analgesics with less abuse liability are badly needed. Currently, the most promising perspectives appear to be augmenting endogenous opioid actions and selectively targeting pathological conformations of peripheral opioid receptors.

KEYWORDS:

• Acidosis
• addiction
• analgesia
• biased signaling
• constipation
• G-protein coupled receptors
• inflammation
• injury
• opioid
• pain
• respiratory depression
• sedation

Article highlights

• Tissue injury leads to excitation of peripheral sensory neurons (nociceptors). These signals are transferred to the spinal cord and brain, where they are integrated to generate the perception of pain. Because central sensitization critically depends on the peripheral drive by nociceptors, therapeutic interventions targeting such neurons are promising. Endogenous mechanisms counteract pain at peripheral and central levels. In injured peripheral tissue, immune cell-derived opioid peptides (endorphin) can silence nociceptors carrying opioid receptors.

• Opioid receptors are expressed by central and peripheral neurons. Agonist binding promotes intracellular coupling of G_i/o proteins to the receptor. Downstream signaling pathways lead to blockade of neuronal excitation and analgesia. Subsequent binding of arrestins triggers receptor desensitization and internalization.

• Pathological (e.g. inflammatory) pain can lead to enhanced opioid receptor function. Thereby, significant analgesic effects are mediated by opioid receptors localized on peripheral sensory neurons.

• Opioid agonists inhibit clinical pain after peripheral (topical, intraarticular), neuraxial (intrathecal, epidural, intracerebroventricular), or systemic (intravenous, oral, subcutaneous, sublingual, transdermal) administration. Adverse effects include respiratory depression, sedation, addiction, nausea, and constipation. Opioids alone are not appropriate for the treatment of chronic non-cancer pain. Species differences must be considered when comparing preclinical with clinical findings.

• Current research strategies aim at reducing side effects by augmenting endogenous opioid mechanisms, biased ligands and selective activation of peripheral opioid receptors. Both pharmacokinetic and pharmacodynamic concepts are pursued.

• Novel drugs for clinical application have not yet arisen from those strategies, although some compounds have advanced to clinical phase III trials.

This box summarizes key points contained in the article.

Declaration of interest

C. Stein is listed as inventor on US Patent 9 1331 20 B2 and European Patent 2 801 046.

The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was funded by Bundesministerium für Bildung und Forschung 0316177B/C1, 01EC1403E, 01EC1403F, European Commission EU FP7-HEALTH-2013-INNOVATION-1; No. 602891-2, and Helmholtz-Gemeinschaft Helmholtz Virtual Institute ‘Multifunctional Biomaterials for Medicine’