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A novel alternative to conventional pain killers?



The 2024 Global Year will examine what is known about sex and gender differences in pain perception and modulation and address sex-and gender-related disparities in both the research and treatment of pain.

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In a recent clinical study we showed for the first time that a large fraction (about one third) of pain relief produced by morphine (the gold standard among pain killers) is mediated by opioid receptors outside the brain. In patients undergoing knee replacement surgery, the blockade of such peripheral opioid receptors by methylnaltrexone (an opioid receptor antagonist that does not enter the brain) led to a 40 % higher demand for morphine in order to produce satisfactory pain relief (analgesia) after the operation (Jagla et al. 2014). This suggests that future drugs designed to exclusively activate peripheral opioid receptors should be able to significantly diminish pain without eliciting central opioid side effects.

Morphine or related opioid drugs (oxycodone, fentanyl) are used for treatment of severe pain associated with cancer or surgery. However, opioids and other pain killers (such as aspirin, diclofenac, coxibs) have serious, and sometimes life-threatening side effects (arrest of breathing, nausea, drowsiness, dependence, addiction, bleeding, heart attack, stroke). For over 25 years our research team has explored basic mechanisms underlying peripherally mediated opioid analgesia in injured and inflamed tissues. Initially, we showed that very small doses of morphine injected into inflamed rat paws or into inflamed knee joints of patients produced potent pain relief (Stein et al. 1989; Stein et al. 1991; Stein et al. 1999). We demonstrated that these effects are mediated by opioid receptors localized on peripheral terminals of sensory nerve fibers (Stein et al. 1990), that these receptors are upregulated in injured tissue and that they function by modulating ion channels (Stein et al. 2003; Nockemann et al. 2013). We also detected the body’s own reaction partners of these receptors (endorphins, enkephalins) in inflammatory cells, and showed that they counteract pain in animals and humans (Stein et al. 1990; Stein et al. 1993; Stein 1995; Machelska et al. 1998; Rittner et al. 2009; Schreiter et al. 2012). Interestingly, tolerance (a waning potency of opioids with prolonged administration) develops much less at peripheral opioid receptors, apparently due to accelerated recycling of “fresh” receptors within nerve terminals (Zöllner et al. 2008). Peripheral opioids not only reduce pain but also counteract the inflammatory process itself (Stein & Machelska 2011; Stein & Küchler 2013). Thus, the future development of opioids that act outside the brain is aiming to improve the treatment of pain, and to reduce side effects generating significant costs and societal burden.

Our recent study (Jagla et al. 2014) is a successful example of “bench-to-bedside” translational research. The results have now confirmed the enormous potential for novel, peripherally selective opioid drugs in human patients. In addition, our data suggest that treatment of patients with methylnaltrexone (for opioid-induced constipation) carries a risk of attenuating the analgesic effects of opioids. By the present and previous studies, we hope to contribute incremental progress towards safer pain killers.

About Christoph Stein

Christoph SteinProf Dr Christoph Stein is Professor and Chair at the Department of Anesthesiology and Intensive Care Medicine, Freie Universität Berlin, Germany.



Stein C, Millan MJ, Shippenberg TS, Peter K, & Herz A (1989). Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther, 248 (3), 1269-75 PMID: 2539460

Stein C, Hassan AH, Przewłocki R, Gramsch C, Peter K, & Herz A (1990). Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci USA , 87 (15), 5935-9 PMID: 1974052

Stein, C., Comisel, K., Haimerl, E., Yassouridis, A., Lehrberger, K., Herz, A., & Peter, K. (1991). Analgesic Effect of Intraarticular Morphine after Arthroscopic Knee Surgery N Engl J Med , 325 (16), 1123-1126 DOI: 10.1056/NEJM199110173251602

Stein, C., Hassan, A., Lehrberger, K., Stein, C., Giefing, J., & Yassouridis, A. (1993). Local analgesic effect of endogenous opioid peptides Lancet, 342 (8867), 321-324 DOI: 10.1016/0140-6736(93)91471-W

Stein C: Mechanisms of disease: The control of pain in peripheral tissue by opioids (1995). N Engl J Med, 332(25):1685‑1690

Stein C, Pflüger M, Yassouridis A, Hoelzl J, Lehrberger K, Welte C, Hassan AHS (1996). No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J Clin Invest, 98:793‑799

Machelska H, Cabot PJ, Mousa SA, Zhang Q, Stein C (1998). Pain control in inflammation governed by selectins. Nature Med, 4(12):1425-1428.

Stein A, Yassouridis A, Szopko C, Helmke K, Stein C (1999). Intraarticular morphine versus dexamethasone in chronic arthritis. Pain, 83(3):525-532

Stein C, Schäfer M, Machelska H (2003). Attacking pain at its source: new perspectives on opioids. Nature Med, 9(8):1003-1008

Zöllner C, Mousa SA, Fischer O, Rittner HL, Shaqura M, Brack A, Shakibaei M, Binder W, Urban F, Stein C, Schäfer M (2008). Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain. J Clin Invest; 118(3):1065-1073

Rittner HL, Hackel D, Voigt P, Mousa S, Stolz A, Labuz D, Schäfer M, Schaefer M, Stein C, Brack A (2009).  Mycobacteria attenuate nociceptive responses by formyl peptide receptor-triggered opioid peptide release from neutrophils. PLoS Pathog; 5(4):e1000362

Stein C, Machelska H (2011). Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacol Rev; 63:860-881

Schreiter A, Gore C, Labuz D, Fournie-Zaluski MC, Roques BP, Stein C, Machelska H (2012). Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue. FASEB J; 26(12):5161-71. PMID: 22923332

Nockemann D, Rouault M, Labuz D, Hublitz P, McKnelly K, Reis FC, Stein C, Heppenstall PA (2013). The K+ channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia. EMBO Mol Med; 5:1263-77. PMID: 23818182

Stein C, Küchler S. (2013). Targeting inflammation and wound healing by opioids. Trends Pharmacol Sci; 34(6):303-312. PMID: 23602130

Jagla C, Martus P, & Stein C (2014). Peripheral opioid receptor blockade increases postoperative morphine demands–a randomized, double-blind, placebo-controlled trial. Pain, 155 (10), 2056-62 PMID: 25046272

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