Potent Opioid Analgesia without Respiratory Depression Could It Be Possible? Albert Dahan, M.D., Ph.D.
T
he first known written reference to the medicinal use of the opium poppy dates from 4,000 BC in Sumerian clay tablets.1 We have come a long way since the use of opium sap, but despite its many disadvantages, we still abundantly use drugs that activate the endogenous opioid system. These drugs are identical (e.g., morphine) or very much alike the many active alkaloids that are present in opium sap. In fact, in contemporary medicine, opioid analgesics remain the most potent painkillers that we have and consequently that we use in the pharmacologic treatment of acute (perioperative) and chronic pain. However, the use of opioids comes at the price of serious adverse effects, including potentially lifethreatening respiratory depression and the potential for abuse and addiction. Inadvertent overdosing resulting in unintentional mortality from prescription opioids for the treatment of chronic pain has increased dramatically over the last decades.2,3 This is partly attributed to an increased awareness by clinicians to diagnose and treat chronic pain and pressure from the industry to treat moderate to severe pain with opioids.2 In this issue of Anesthesiology, Sitbon et al.4 present experimental data on a small peptide, STR-324, a stable analog of opiorphin. Opiorphin is an inhibitor of various peptidases that break down met-enkephalin (fig. 1A) to inactive metabolites. The enkephalins are endogenous analgesic peptides involved in endogenous opioidergic pain pathways. The authors show that the continuous infusion of STR-324 produces long-term naloxone-reversible pain relief in a model of postoperative pain. This is important, but equally important is that novel analgesic agents that interact with the opioid system should produce less respiratory depression than commonly used opioids (such as morphine), combined with a lesser abuse potential. To address the former issue, Sitbon
et al. measured respiratory variables in their study animals during infusion of low- and high-dose STR324 and observed no significant changes in the respiratory rate and oxygen saturation using plethysmographic measurements at the animals’ tail. This is reassuring, but it is important that such observations are replicated in human studies. It is my experience that claims of reduced or absent respiratory effects of analgesic drugs acting within the opioid receptor system are often refuted in human studies. Indeed, some respiratory depression is expected from drugs that enhance enkephalin activity. As discussed by Pattinson,5 nearly 98% of type 1 carotid body cells exhibit encephalin immunoreactivity and administration of enkephalin inhibits carotid body activity; the carotid bodies play a crucial role in the ventilatory response to hypoxia. Also, the brainstem contains enkephalin-sensitive respiratory neurons, with slowing of respiratory rhythm observed after application of the μ-opioid receptor agonist DAMGO (a stable analog of leu- and met-enkephalin) to brain slices that contain the pre-Bötzinger complex, an area of the brain involved in respiratory rhythmogenesis.5 This suggests that at least a (small or large) respiratory effect from STR-324 should have occurred in the current study. Possibly, more rigorous tests, such as measurements of the ventilatory responses to inhaled carbon dioxide, would have revealed such effects. Important to this discussion, as mentioned by the authors, is that endogenous enkephalins have a higher affinity for δ-opioid receptors than for μ-opioid receptors. It may well be that δ-opioid receptor activity (1) counteracts the adverse effects from μ-opioid receptor activation6 and (2) results in the need for less μ-opioid receptor activity for optimal analgesic responses.4 Both mechanisms may lead to less respiratory depression than for pure μ-opioid receptor
“[Could] novel analgesics... produce less respiratory depression than commonly used opioids…combined with a lesser abuse potential?”
Image: © ThinkStock. Corresponding article on page 1017. Accepted for publication June 20, 2016. Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2016; 125:841-3
Anesthesiology, V 125 • No 5 841
November 2016
Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Editorial Views
Fig. 1. (A) Met-enkephalin acts at μ- and δ-opioid receptors albeit with higher affinity at the δ-opioid receptor. Various peptidases cause the breakdown of met-enkephalin to inactive metabolites Tyr-Gly-Gly and Tyr. This breakdown process is inhibited by opiorphin (red arrow). (B) Activation of the μ-opioid receptor by morphine causes activation of the G-coupled protein pathway (leading to analgesia) and the β-arrestin pathway (involved in the development of opioid tolerance and respiratory depression). G-protein biased ligands selectively activate the G-coupled protein pathway, causing less tolerance and respiratory depression.
agonists, such as morphine and fentanyl. Given all the available data, I believe that additional animal and human studies are required before definitive conclusions can be drawn regarding the side effect profile of STR-324 and related compounds. Acute pain and chronic pain are serious conditions that require immediate and appropriate actions, which commonly include opioid analgesics. Because of the abundant and potentially fatal adverse effects of classical μ-opioid receptors, there is an ongoing search for drugs that interact with the opioid receptor system but that cause less adverse effects. As mentioned above, Sitbon et al.4 provide promising data on a novel class of analgesics acting via enkephalinergic pathways. I would like to briefly mention one other important new development, the design of so-called biased-opioid-receptor ligands. Biased ligands are functionally selective opioid receptor agonists causing biased activity at the G-protein or β-arrestin intracellular pathways. Both intracellular pathways Anesthesiology 2016; 125:841-3 842
are recruited after opioid receptor activation by commonly used opioids (nonbiased opioids). G-protein biased ligands (i.e., ligands that activate the opioid receptor without recruitment of the β-arrestin pathway) demonstrate analgesia with less respiratory depression and less opioid tolerance development (fig. 1B).7 A recent phase II trial investigated the effect of an experimental biased ligand at the μ-opioid receptor in acute pain after bunionectomy.8 The drug produced potent analgesia without serious adverse effects with tolerability similar to morphine. Also for this drug, rigorous respiratory experiments in humans are required before we can definitely state that we are able to treat pain with potent analgesics that interact within the opioid receptor system with no or at least limited respiratory effects, even at high and supraclinical doses.
Competing Interests In the last 20 yr, Dr. Dahan published various studies on the effect of experimental and existing opioid receptor agonists and opioid reversal agents on the ventilatory control system. Albert Dahan
Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Editorial View
Several of these studies were sponsored by pharmaceutical companies, such as Grünenthal GmbH, Aachen, Germany; Mundipharma Research Ltd., Cambridge, United Kingdom; and Galleon Pharmaceuticals Inc., Horsham, Pennsylvania.
Correspondence Address correspondence to Dr. Dahan: [email protected]
References 1. Bovill JG: Opium – a drug ancient and modern, Advances in Anesthesia and Analgesia. Edited by Dahan A, van Kleef JW. Leiden, Leiden University, 2007, pp 7–27 2. Okie S: A flood of opioids, a rising tide of deaths. N Engl J Med 2010; 363:1981–5 3. Kharasch ED, Brunt LM: Perioperative opioids and public health. Anesthesiology 2016; 124:960–5 4. Sitbon P, Van Elstraete A, Hamdi L, Juarez-Perez V, Mazoit J-X, Benhamou D, Rougeot C: STR-324, a stable analog of
Anesthesiology 2016; 125:841-3 843
opiorphin, causes analgesia in postoperative pain by activating endogenous opioid receptor–dependent pathways. Anesthesiology 2016; 125:1017–29 5. Pattinson KT: Opioids and the control of respiration. Br J Anaesth 2008; 100:747–58 6. Su YF, McNutt RW, Chang KJ: δ-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception. J Pharmacol Exp Ther 1998; 287:815–23 7. DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD: A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther 2013; 344:708–17 8. Viscusi ER, Webster L, Kuss M, Daniels S, Bolognese JA, Zuckerman S, Soergel DG, Subach RA, Cook E, Skobieranda F: A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain. Pain 2016; 157:264–72
Albert Dahan
Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
T
he first known written reference to the medicinal use of the opium poppy dates from 4,000 BC in Sumerian clay tablets.1 We have come a long way since the use of opium sap, but despite its many disadvantages, we still abundantly use drugs that activate the endogenous opioid system. These drugs are identical (e.g., morphine) or very much alike the many active alkaloids that are present in opium sap. In fact, in contemporary medicine, opioid analgesics remain the most potent painkillers that we have and consequently that we use in the pharmacologic treatment of acute (perioperative) and chronic pain. However, the use of opioids comes at the price of serious adverse effects, including potentially lifethreatening respiratory depression and the potential for abuse and addiction. Inadvertent overdosing resulting in unintentional mortality from prescription opioids for the treatment of chronic pain has increased dramatically over the last decades.2,3 This is partly attributed to an increased awareness by clinicians to diagnose and treat chronic pain and pressure from the industry to treat moderate to severe pain with opioids.2 In this issue of Anesthesiology, Sitbon et al.4 present experimental data on a small peptide, STR-324, a stable analog of opiorphin. Opiorphin is an inhibitor of various peptidases that break down met-enkephalin (fig. 1A) to inactive metabolites. The enkephalins are endogenous analgesic peptides involved in endogenous opioidergic pain pathways. The authors show that the continuous infusion of STR-324 produces long-term naloxone-reversible pain relief in a model of postoperative pain. This is important, but equally important is that novel analgesic agents that interact with the opioid system should produce less respiratory depression than commonly used opioids (such as morphine), combined with a lesser abuse potential. To address the former issue, Sitbon
et al. measured respiratory variables in their study animals during infusion of low- and high-dose STR324 and observed no significant changes in the respiratory rate and oxygen saturation using plethysmographic measurements at the animals’ tail. This is reassuring, but it is important that such observations are replicated in human studies. It is my experience that claims of reduced or absent respiratory effects of analgesic drugs acting within the opioid receptor system are often refuted in human studies. Indeed, some respiratory depression is expected from drugs that enhance enkephalin activity. As discussed by Pattinson,5 nearly 98% of type 1 carotid body cells exhibit encephalin immunoreactivity and administration of enkephalin inhibits carotid body activity; the carotid bodies play a crucial role in the ventilatory response to hypoxia. Also, the brainstem contains enkephalin-sensitive respiratory neurons, with slowing of respiratory rhythm observed after application of the μ-opioid receptor agonist DAMGO (a stable analog of leu- and met-enkephalin) to brain slices that contain the pre-Bötzinger complex, an area of the brain involved in respiratory rhythmogenesis.5 This suggests that at least a (small or large) respiratory effect from STR-324 should have occurred in the current study. Possibly, more rigorous tests, such as measurements of the ventilatory responses to inhaled carbon dioxide, would have revealed such effects. Important to this discussion, as mentioned by the authors, is that endogenous enkephalins have a higher affinity for δ-opioid receptors than for μ-opioid receptors. It may well be that δ-opioid receptor activity (1) counteracts the adverse effects from μ-opioid receptor activation6 and (2) results in the need for less μ-opioid receptor activity for optimal analgesic responses.4 Both mechanisms may lead to less respiratory depression than for pure μ-opioid receptor
“[Could] novel analgesics... produce less respiratory depression than commonly used opioids…combined with a lesser abuse potential?”
Image: © ThinkStock. Corresponding article on page 1017. Accepted for publication June 20, 2016. Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2016; 125:841-3
Anesthesiology, V 125 • No 5 841
November 2016
Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Editorial Views
Fig. 1. (A) Met-enkephalin acts at μ- and δ-opioid receptors albeit with higher affinity at the δ-opioid receptor. Various peptidases cause the breakdown of met-enkephalin to inactive metabolites Tyr-Gly-Gly and Tyr. This breakdown process is inhibited by opiorphin (red arrow). (B) Activation of the μ-opioid receptor by morphine causes activation of the G-coupled protein pathway (leading to analgesia) and the β-arrestin pathway (involved in the development of opioid tolerance and respiratory depression). G-protein biased ligands selectively activate the G-coupled protein pathway, causing less tolerance and respiratory depression.
agonists, such as morphine and fentanyl. Given all the available data, I believe that additional animal and human studies are required before definitive conclusions can be drawn regarding the side effect profile of STR-324 and related compounds. Acute pain and chronic pain are serious conditions that require immediate and appropriate actions, which commonly include opioid analgesics. Because of the abundant and potentially fatal adverse effects of classical μ-opioid receptors, there is an ongoing search for drugs that interact with the opioid receptor system but that cause less adverse effects. As mentioned above, Sitbon et al.4 provide promising data on a novel class of analgesics acting via enkephalinergic pathways. I would like to briefly mention one other important new development, the design of so-called biased-opioid-receptor ligands. Biased ligands are functionally selective opioid receptor agonists causing biased activity at the G-protein or β-arrestin intracellular pathways. Both intracellular pathways Anesthesiology 2016; 125:841-3 842
are recruited after opioid receptor activation by commonly used opioids (nonbiased opioids). G-protein biased ligands (i.e., ligands that activate the opioid receptor without recruitment of the β-arrestin pathway) demonstrate analgesia with less respiratory depression and less opioid tolerance development (fig. 1B).7 A recent phase II trial investigated the effect of an experimental biased ligand at the μ-opioid receptor in acute pain after bunionectomy.8 The drug produced potent analgesia without serious adverse effects with tolerability similar to morphine. Also for this drug, rigorous respiratory experiments in humans are required before we can definitely state that we are able to treat pain with potent analgesics that interact within the opioid receptor system with no or at least limited respiratory effects, even at high and supraclinical doses.
Competing Interests In the last 20 yr, Dr. Dahan published various studies on the effect of experimental and existing opioid receptor agonists and opioid reversal agents on the ventilatory control system. Albert Dahan
Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Editorial View
Several of these studies were sponsored by pharmaceutical companies, such as Grünenthal GmbH, Aachen, Germany; Mundipharma Research Ltd., Cambridge, United Kingdom; and Galleon Pharmaceuticals Inc., Horsham, Pennsylvania.
Correspondence Address correspondence to Dr. Dahan: [email protected]
References 1. Bovill JG: Opium – a drug ancient and modern, Advances in Anesthesia and Analgesia. Edited by Dahan A, van Kleef JW. Leiden, Leiden University, 2007, pp 7–27 2. Okie S: A flood of opioids, a rising tide of deaths. N Engl J Med 2010; 363:1981–5 3. Kharasch ED, Brunt LM: Perioperative opioids and public health. Anesthesiology 2016; 124:960–5 4. Sitbon P, Van Elstraete A, Hamdi L, Juarez-Perez V, Mazoit J-X, Benhamou D, Rougeot C: STR-324, a stable analog of
Anesthesiology 2016; 125:841-3 843
opiorphin, causes analgesia in postoperative pain by activating endogenous opioid receptor–dependent pathways. Anesthesiology 2016; 125:1017–29 5. Pattinson KT: Opioids and the control of respiration. Br J Anaesth 2008; 100:747–58 6. Su YF, McNutt RW, Chang KJ: δ-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception. J Pharmacol Exp Ther 1998; 287:815–23 7. DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD: A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther 2013; 344:708–17 8. Viscusi ER, Webster L, Kuss M, Daniels S, Bolognese JA, Zuckerman S, Soergel DG, Subach RA, Cook E, Skobieranda F: A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain. Pain 2016; 157:264–72
Albert Dahan
Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
