- Email: [email protected]
Morphine is not a prodrug
Correspondence
| 1005
Declaration of interest
Reference
None declared.
1. McCullough AL, Haycock JC, Forward DP, Moran CG. Major trauma networks in England. Br J Anaesth 2014; 113: 202–6 doi:10.1093/bja/aev124
Morphine is not a prodrug A. Dahan1,* and J. Loetsch2 1
Leiden, The Netherlands, and 2Frankfurt am Main, Germany
*E-mail: [email protected]
effects such as analgesia, respiratory depression, nausea and vomiting are produced (the transfer half-lives are 1.6–4.8 h for morphine10 17 18 and 6.2–8.2 h for M6G9 12 17). Indeed, the clinical effects of M6G after acute administration involve an important peripheral component.19 When compared head to head with morphine in a large study enrolling 517 patients after major abdominal surgery, M6G proved less efficacious than morphine in patient-controlled analgesia.20 In this study, the equianalgesic M6G:morphine dose ratios ranged from 3:1 during the titration phase to 1.7:1 during the first 24 h and 1.3:1 during the second 24 h of the study. This indicates that the production of M6G from morphine during a 48-h period is not enough to significantly contribute to the analgesic effects induced by morphine itself. Furthermore, M6Ginduced analgesia had a slower onset than morphine-induced analgesia, which relates to its slower transfer across the blood– brain barrier.21 These clinical data indicate that morphine is well able to produce clinical effects without a necessity of prior glucuronidation at its free hydroxyl group at the sixth carbonic atom. An effectiveness of morphine not requiring mediation via M6G is further emphasized by its well-documented activity in rats, which cannot form the 6-glucuronide from morphine, only the 3-glucuronide. This owes to the fact that aromatic hydroxyl groups are glucuronidated more easily than alicyclic hydroxyl groups and therefore, also in humans, more morphine-3-glucuronide (M3G) than M6G is formed from morphine,22–26 while the rat uridine diphosphate glucuronosyltransferase is usually unable to form the 6-glucuronide.27 M3G, however, has significantly higher plasma concentrations than M6G in humans, lacks opioid effects, but may produce anti-analgesic and neuro-excitatory clinical effects.28 Taken together, the above-presented evidence seems to support that following short-term (up to 48 h) i.v. administrations of morphine, the contribution of M6G is limited and not dominant. This relates to acute pain treatment in the perioperative patient. After long-term oral administration of morphine, the relative contribution of M6G to the analgesia and side effects observed after morphine administration might become more substantial since its plasma concentration may now exceed those of morphine,26 in particular when its renal elimination is compromised. However, the effects of morphine itself remain significant. Thus evidence mainly gathered from direct assessments of the pharmacokinetics and pharmacodynamics after the administration of M6G itself, rather than obtained from interpreting the contributions of M6G after the administration of morphine,
Downloaded from http://bja.oxfordjournals.org/ at University of Texas at Austin on June 5, 2015
Editor–A prodrug is defined as a medication that is administered in an inactive or less than fully active form and is then converted to its active form through a normal metabolic process (http://en. wikipedia.org/wiki/Prodrug). The title of a recent publication in the British Journal of Analgesia, ‘Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide’ reminds us of this definition.1 The authors of the article performed a literature-based analysis of blood and cerebrospinal fluid concentrations of morphine and its major glucuronides and, based on specific assumptions regarding receptor binding, came to the conclusion that ‘when administering morphine to patients, the analgesic effect is mainly caused by [morphine-6-glucuronide] M6G instead of morphine itself, irrespective of the route of administration’.1 The pharmacodynamic activity of opioid glucuronides was first reported in the late 1960s.2–4 Following a publication about the analgesic activity of M6G after injection to healthy volunteers,5 discussion about the clinical activity of M6G became intense during the 1990s and early years of the new millennium. This discussion was further fuelled by a demonstration that intrathecally injected M6G is clinically active.6 As studies employing direct administration of M6G also indicated its activity as an opioid,5 scientific interest extended towards (i) the relative contribution of M6G to the clinical effects of morphine and (ii) its possible utility as an opioid analgesic. Based mainly on observations of plasma concentration ratios, the hypothesis was raised that M6G plays a major if not critical role in the effects of morphine, which 15 yr later seems to have been revived. However, most studies that employed direct administration of M6G came to the conclusion that M6G, while exerting opioid effects, often contributes little to the effects of morphine. First, it lacks a reproducible major contribution to the effects following acute i.v. administration of morphine.7–13 For example, the contribution of M6G to the effects of a single i.v. dose of 0.1 mg kg−1 of morphine has been calculated as amounting to 10%, which may increase to 20% in patients with severe renal impairment,12 and after four i.v. injections of 0.1 mg kg−1 morphine at 8-h intervals the contribution of M6G to the analgesia increased to 20%. Second, during chronic morphine treatment its contribution depends on its elimination and becomes relatively important when renal function is compromised.14–16 Among important reasons for this modest contribution, in particular to the acute effects of morphine, is the very slow equilibration of M6G between plasma and effect sites located in the central nervous system, where most clinical opioid
1006
| Correspondence
clearly indicates that M6G cannot be considered as the main active principle in morphine treatment. Hence morphine cannot be considered a prodrug, which, although not explicitly elaborated, follows from the conclusions of the recent publication in this journal.1
Declaration of interest None declared.
References
doi:10.1093/bja/aev125
Downloaded from http://bja.oxfordjournals.org/ at University of Texas at Austin on June 5, 2015
1. Klimas R, Mikus G. Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide. Br J Anaesth 2014; 113: 935–44 2. Kamata O, Watanabe S, Ishii S, et al. Analgesic effect of morphine glucuronides. In: Proceedings of the 89th Meeting of the Pharmacology Society of Japan. 1969: 443 3. Shimomura K, Kamata O, Ueki S, Ida S, Oguri K. Analgesic effect of morphine glucuronides. Tohoku J Exp Med 1971; 105: 45–52 4. Yoshimura H, Ida S, Oguri K, Tsukamoto H. Biochemical basis for analgesic activity of morphine-6- glucuronide. I. Penetration of morphine- 6-glucuronide in the brain of rats. Biochem Pharmacol 1973; 22: 1423–30 5. Osborne R, Thompson P, Joel S, Trew D, Patel N, Slevin M. The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol 1992; 34: 130–8 6. Hanna MH, Peat SJ, Woodham M, Knibb A, Fung C. Analgesic efficacy and CSF pharmacokinetics of intrathecal morphine6-glucuronide: comparison with morphine. Br J Anaesth 1990; 64: 547–50 7. Lötsch J, Kobal G, Stockmann A, Brune K, Geisslinger G. Lack of analgesic activity of morphine-6-glucuronide after shortterm intravenous administration in healthy volunteers. Anesthesiology 1997; 87: 1348–58 8. Lötsch J, Skarke C, Schmidt H, Liefhold J, Geisslinger G. Pharmacokinetic modeling to predict morphine and morphine6-glucuronide plasma concentrations in healthy young volunteers. Clin Pharmacol Ther 2002; 72: 151–62 9. Skarke C, Darimont J, Schmidt H, Geisslinger G, Lötsch J. Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 2003; 73: 107–21 10. Sarton E, Olofsen E, Romberg R, et al. Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology 2000; 93: 1245–54 11. Romberg R, Olofsen E, Sarton E, Teppema L, Dahan A. Pharmacodynamic effect of morphine-6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers. Anesthesiology 2003; 99: 788–98 12. Romberg R, Olofsen E, Sarton E, den Hartigh J, Taschner PE, Dahan A. Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences. Anesthesiology 2004; 100: 120–33
13. Romberg R, van Dorp E, Hollander J, et al. A randomized, double-blind, placebo-controlled pilot study of IV morphine6-glucuronide for postoperative pain relief after knee replacement surgery. Clin J Pain 2007; 23: 197–203 14. Pauli-Magnus C, Hofmann U, Mikus G, Kuhlmann U, Mettang T. Pharmacokinetics of morphine and its glucuronides following intravenous administration of morphine in patients undergoing continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 1999; 14: 903–9 15. Peterson GM, Randall CT, Paterson J. Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship to renal function and route of administration. Eur J Clin Pharmacol 1990; 38: 121–4 16. Angst MS, Buehrer M, Lötsch J. Insidious intoxication after morphine treatment in renal failure: delayed onset of morphine-6-glucuronide action. Anesthesiology 2000; 92: 1473–6 17. Lötsch J, Skarke C, Schmidt H, Groesch S, Geisslinger G. The transfer half-life of morphine-6-beta-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers. Anesthesiology 2001; 95: 1329–38 18. Dershwitz M, Walsh JL, Morishige RJ, et al. Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers. Anesthesiology 2000; 93: 619–28 19. Tegeder I, Meier S, Burian M, Schmidt H, Geisslinger G, Lötsch J. Peripheral opioid analgesia in experimental human pain models. Brain 2003; 126: 1092–102 20. Binning AR, Przesmycki K, Sowinski P, et al. A randomised controlled trial on the efficacy and side-effect profile (nausea/vomiting/sedation) of morphine-6-glucuronide versus morphine for post-operative pain relief after major abdominal surgery. Eur J Pain 2011; 15: 402–8 21. Lötsch J. Pharmacokinetic-pharmacodynamic modeling of opioids. J Pain Symptom Manage 2005; 29: S90–103 22. Lötsch J, Stockmann A, Kobal G, et al. Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers. Clin Pharmacol Ther 1996; 60: 316–25 23. Lötsch J, Skarke C, Liefhold J, Geisslinger G. Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. Clin Pharmacokinet 2004; 43: 983–1013 24. Lötsch J. Opioid metabolites. J Pain Symptom Manage 2005; 29: S10–24 25. Lötsch J, Weiss M, Kobal G, Geisslinger G. Pharmacokinetics of morphine-6-glucuronide and its formation from morphine after intravenous administration. Clin Pharmacol Ther 1998; 63: 629–39 26. Lötsch J, Weiss M, Ahne G, Kobal G, Geisslinger G. Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers. Anesthesiology 1999; 90: 1026–38 27. Milne RW, Nation RL, Somogyi AA. The disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine. Drug Metab Rev 1996; 28: 345–472 28. Heger S, Maier C, Otter K, Helwig U, Suttorp M. Morphine induced allodynia in a child with brain tumour. BMJ 1999; 319: 627–9
| 1005
Declaration of interest
Reference
None declared.
1. McCullough AL, Haycock JC, Forward DP, Moran CG. Major trauma networks in England. Br J Anaesth 2014; 113: 202–6 doi:10.1093/bja/aev124
Morphine is not a prodrug A. Dahan1,* and J. Loetsch2 1
Leiden, The Netherlands, and 2Frankfurt am Main, Germany
*E-mail: [email protected]
effects such as analgesia, respiratory depression, nausea and vomiting are produced (the transfer half-lives are 1.6–4.8 h for morphine10 17 18 and 6.2–8.2 h for M6G9 12 17). Indeed, the clinical effects of M6G after acute administration involve an important peripheral component.19 When compared head to head with morphine in a large study enrolling 517 patients after major abdominal surgery, M6G proved less efficacious than morphine in patient-controlled analgesia.20 In this study, the equianalgesic M6G:morphine dose ratios ranged from 3:1 during the titration phase to 1.7:1 during the first 24 h and 1.3:1 during the second 24 h of the study. This indicates that the production of M6G from morphine during a 48-h period is not enough to significantly contribute to the analgesic effects induced by morphine itself. Furthermore, M6Ginduced analgesia had a slower onset than morphine-induced analgesia, which relates to its slower transfer across the blood– brain barrier.21 These clinical data indicate that morphine is well able to produce clinical effects without a necessity of prior glucuronidation at its free hydroxyl group at the sixth carbonic atom. An effectiveness of morphine not requiring mediation via M6G is further emphasized by its well-documented activity in rats, which cannot form the 6-glucuronide from morphine, only the 3-glucuronide. This owes to the fact that aromatic hydroxyl groups are glucuronidated more easily than alicyclic hydroxyl groups and therefore, also in humans, more morphine-3-glucuronide (M3G) than M6G is formed from morphine,22–26 while the rat uridine diphosphate glucuronosyltransferase is usually unable to form the 6-glucuronide.27 M3G, however, has significantly higher plasma concentrations than M6G in humans, lacks opioid effects, but may produce anti-analgesic and neuro-excitatory clinical effects.28 Taken together, the above-presented evidence seems to support that following short-term (up to 48 h) i.v. administrations of morphine, the contribution of M6G is limited and not dominant. This relates to acute pain treatment in the perioperative patient. After long-term oral administration of morphine, the relative contribution of M6G to the analgesia and side effects observed after morphine administration might become more substantial since its plasma concentration may now exceed those of morphine,26 in particular when its renal elimination is compromised. However, the effects of morphine itself remain significant. Thus evidence mainly gathered from direct assessments of the pharmacokinetics and pharmacodynamics after the administration of M6G itself, rather than obtained from interpreting the contributions of M6G after the administration of morphine,
Downloaded from http://bja.oxfordjournals.org/ at University of Texas at Austin on June 5, 2015
Editor–A prodrug is defined as a medication that is administered in an inactive or less than fully active form and is then converted to its active form through a normal metabolic process (http://en. wikipedia.org/wiki/Prodrug). The title of a recent publication in the British Journal of Analgesia, ‘Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide’ reminds us of this definition.1 The authors of the article performed a literature-based analysis of blood and cerebrospinal fluid concentrations of morphine and its major glucuronides and, based on specific assumptions regarding receptor binding, came to the conclusion that ‘when administering morphine to patients, the analgesic effect is mainly caused by [morphine-6-glucuronide] M6G instead of morphine itself, irrespective of the route of administration’.1 The pharmacodynamic activity of opioid glucuronides was first reported in the late 1960s.2–4 Following a publication about the analgesic activity of M6G after injection to healthy volunteers,5 discussion about the clinical activity of M6G became intense during the 1990s and early years of the new millennium. This discussion was further fuelled by a demonstration that intrathecally injected M6G is clinically active.6 As studies employing direct administration of M6G also indicated its activity as an opioid,5 scientific interest extended towards (i) the relative contribution of M6G to the clinical effects of morphine and (ii) its possible utility as an opioid analgesic. Based mainly on observations of plasma concentration ratios, the hypothesis was raised that M6G plays a major if not critical role in the effects of morphine, which 15 yr later seems to have been revived. However, most studies that employed direct administration of M6G came to the conclusion that M6G, while exerting opioid effects, often contributes little to the effects of morphine. First, it lacks a reproducible major contribution to the effects following acute i.v. administration of morphine.7–13 For example, the contribution of M6G to the effects of a single i.v. dose of 0.1 mg kg−1 of morphine has been calculated as amounting to 10%, which may increase to 20% in patients with severe renal impairment,12 and after four i.v. injections of 0.1 mg kg−1 morphine at 8-h intervals the contribution of M6G to the analgesia increased to 20%. Second, during chronic morphine treatment its contribution depends on its elimination and becomes relatively important when renal function is compromised.14–16 Among important reasons for this modest contribution, in particular to the acute effects of morphine, is the very slow equilibration of M6G between plasma and effect sites located in the central nervous system, where most clinical opioid
1006
| Correspondence
clearly indicates that M6G cannot be considered as the main active principle in morphine treatment. Hence morphine cannot be considered a prodrug, which, although not explicitly elaborated, follows from the conclusions of the recent publication in this journal.1
Declaration of interest None declared.
References
doi:10.1093/bja/aev125
Downloaded from http://bja.oxfordjournals.org/ at University of Texas at Austin on June 5, 2015
1. Klimas R, Mikus G. Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide. Br J Anaesth 2014; 113: 935–44 2. Kamata O, Watanabe S, Ishii S, et al. Analgesic effect of morphine glucuronides. In: Proceedings of the 89th Meeting of the Pharmacology Society of Japan. 1969: 443 3. Shimomura K, Kamata O, Ueki S, Ida S, Oguri K. Analgesic effect of morphine glucuronides. Tohoku J Exp Med 1971; 105: 45–52 4. Yoshimura H, Ida S, Oguri K, Tsukamoto H. Biochemical basis for analgesic activity of morphine-6- glucuronide. I. Penetration of morphine- 6-glucuronide in the brain of rats. Biochem Pharmacol 1973; 22: 1423–30 5. Osborne R, Thompson P, Joel S, Trew D, Patel N, Slevin M. The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol 1992; 34: 130–8 6. Hanna MH, Peat SJ, Woodham M, Knibb A, Fung C. Analgesic efficacy and CSF pharmacokinetics of intrathecal morphine6-glucuronide: comparison with morphine. Br J Anaesth 1990; 64: 547–50 7. Lötsch J, Kobal G, Stockmann A, Brune K, Geisslinger G. Lack of analgesic activity of morphine-6-glucuronide after shortterm intravenous administration in healthy volunteers. Anesthesiology 1997; 87: 1348–58 8. Lötsch J, Skarke C, Schmidt H, Liefhold J, Geisslinger G. Pharmacokinetic modeling to predict morphine and morphine6-glucuronide plasma concentrations in healthy young volunteers. Clin Pharmacol Ther 2002; 72: 151–62 9. Skarke C, Darimont J, Schmidt H, Geisslinger G, Lötsch J. Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 2003; 73: 107–21 10. Sarton E, Olofsen E, Romberg R, et al. Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology 2000; 93: 1245–54 11. Romberg R, Olofsen E, Sarton E, Teppema L, Dahan A. Pharmacodynamic effect of morphine-6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers. Anesthesiology 2003; 99: 788–98 12. Romberg R, Olofsen E, Sarton E, den Hartigh J, Taschner PE, Dahan A. Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences. Anesthesiology 2004; 100: 120–33
13. Romberg R, van Dorp E, Hollander J, et al. A randomized, double-blind, placebo-controlled pilot study of IV morphine6-glucuronide for postoperative pain relief after knee replacement surgery. Clin J Pain 2007; 23: 197–203 14. Pauli-Magnus C, Hofmann U, Mikus G, Kuhlmann U, Mettang T. Pharmacokinetics of morphine and its glucuronides following intravenous administration of morphine in patients undergoing continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 1999; 14: 903–9 15. Peterson GM, Randall CT, Paterson J. Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship to renal function and route of administration. Eur J Clin Pharmacol 1990; 38: 121–4 16. Angst MS, Buehrer M, Lötsch J. Insidious intoxication after morphine treatment in renal failure: delayed onset of morphine-6-glucuronide action. Anesthesiology 2000; 92: 1473–6 17. Lötsch J, Skarke C, Schmidt H, Groesch S, Geisslinger G. The transfer half-life of morphine-6-beta-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers. Anesthesiology 2001; 95: 1329–38 18. Dershwitz M, Walsh JL, Morishige RJ, et al. Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers. Anesthesiology 2000; 93: 619–28 19. Tegeder I, Meier S, Burian M, Schmidt H, Geisslinger G, Lötsch J. Peripheral opioid analgesia in experimental human pain models. Brain 2003; 126: 1092–102 20. Binning AR, Przesmycki K, Sowinski P, et al. A randomised controlled trial on the efficacy and side-effect profile (nausea/vomiting/sedation) of morphine-6-glucuronide versus morphine for post-operative pain relief after major abdominal surgery. Eur J Pain 2011; 15: 402–8 21. Lötsch J. Pharmacokinetic-pharmacodynamic modeling of opioids. J Pain Symptom Manage 2005; 29: S90–103 22. Lötsch J, Stockmann A, Kobal G, et al. Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers. Clin Pharmacol Ther 1996; 60: 316–25 23. Lötsch J, Skarke C, Liefhold J, Geisslinger G. Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. Clin Pharmacokinet 2004; 43: 983–1013 24. Lötsch J. Opioid metabolites. J Pain Symptom Manage 2005; 29: S10–24 25. Lötsch J, Weiss M, Kobal G, Geisslinger G. Pharmacokinetics of morphine-6-glucuronide and its formation from morphine after intravenous administration. Clin Pharmacol Ther 1998; 63: 629–39 26. Lötsch J, Weiss M, Ahne G, Kobal G, Geisslinger G. Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers. Anesthesiology 1999; 90: 1026–38 27. Milne RW, Nation RL, Somogyi AA. The disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine. Drug Metab Rev 1996; 28: 345–472 28. Heger S, Maier C, Otter K, Helwig U, Suttorp M. Morphine induced allodynia in a child with brain tumour. BMJ 1999; 319: 627–9