1. Intra-articular injection of morphine: may it play a role? Serbülent Gökhan Beyaz, M.D., Associate Professor Sakarya University Faculty of Medicine Department of Anaesthesiology and Pain Medicine Sakarya, Republic of Turkey sgbeyaz@gmail.com 1

2. Friedrich Serturner (1783-1841) as a pharmacist’s apprentice he was the first person to isolate morphine from opium 2

3. Morphine is highly potent opioid analgesic drug and is principal active agent opium and the prototype opiate. Like other opioids, morphine acts directly on the central nervous system (CNS) to relief pain, and at synapses of the nucleus accumbens in particular. Morphine is highly addictive when compared other substances, and tolerance and physical and psychological dependents develop very rapidly. 3

4. Morphine and endogenous opioids (the enkephalins, dynorphins, and β- endorphin) induce their biological effects by interacting with three major classes of receptors. The -, -, and µ-opioid receptors How do opioid analgesic work? 4

5. There are some preferences for the different endogenous opioid ligands for the different receptors β-endorphin for µ enkephalins for dinorphins for Reisine T et al. Opioid and cannabioid receptors.Curr Opin Neu. 1994 5

6. β-endorphin It binds potently to both the - and µ-receptors, but has a relatively lower affinity for -receptors, suggesting that in peripheral tissues, where β- endorphin is more abundant than enkephalins or dinorphins, it may be an endogenous ligand at the - and µ-receptors. Elvenes J et al. Expression of functional µ-receptors in human osteoarthritic cartilage and chondrocytes. BBRC. 2003 6

7. The three main types of opioid receptors, µ,, and, belong to the family of G protein-coupled receptors inhibit adenylyl cyclase and hence decrease the intracellular level of cyclic AMP. Childers S. Opioid receptor coupled second messenger systems, Lİfe Sci. 1991 7

8. Morphine administration Orally use in tablet but due to its poor bioavailability, oral morphine is only one- eight of the potency parenteral morphine. Parenterally as subcutaneous, intravenous, or epidural injections. Intraoperative applies (Periarticular use and intraarticular use) Chronic pain therapy (Intraarticular use) 8

9. Opioids were believed to act solely on the CNS, producing analgesia by interaction with cerebral and spinal opioid receptors. This dogma was first challenged by an experimental study that recorded directly from the nasal mucosa the local electrophysiological response to painful stimulation of nasal nociceptors. Kobal G. Pain-related electrical potentials of the human nasal mucosa elicited by chemical stimulation. Pain 1985 9

10. Peripheral opioid analgesia Local injection of opioids into peripheral inflamed tissues caused potent local naloxone-reversible antinociception in laboratory animals Stein et al., 1988, 1989; Levine and Taiwo, 1989; Parsons et al., 1990; Kolesnikov et al., 1996; Perrot et al., 1999 10

11. The opioid-induced peripheral anti- nociception occurred preferentially in inflamed tissue. The number of opioid receptors in peripheral tissue is normally low but rapidly increases when inflation comes into play. Hassan et al., 1993; Schafer et al., 1995; Stein et al.,1996 11

12. The physiological importance of peripheral opioid receptors was doubted until in inflammatuar immune cells were identified as the source of endogenous opioid peptides. The release of these endogenous ligands allows for a communication between immune cells and nociceptors. Stein et al., 1995; Schafer et al., 1996, 1997; Machelska et al., 1998, 2002; Rittner et al., 2001 12

13. Hydrophilic morphine metabolite, M6G significantly reduces in inflammatory cutaneous hyperalgesia at plasma concentrations that do not cause CNS effects as confirmed by a lack of change of the pupil size. 13

14. Periarticular apply is easy, reduce opioid requirement, improved patient satisfaction, No infection risk. 0.5% Bupivacaine 200-400 mg Morphine 5 mg Epinephrine 300 µg Metilprednisolon asetat 40 mg Cephuroxime 750 mg Totally SF 60 mL volum 14

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16. intraarticular of alone sufentanil is effective intraarticular of sufentanil plus methylprednisolon is more effective 16

17. OA was induced by transection of the medial meniscotibial ligament. At various times post surgery, the opioid receptor antagonists naloxone or peripherally restricted naloxone methiodide were administered, and pain was assessed. Levels of the µ-opioid receptor were assessed in the nerves innervating the joint. Results: significant joint damage occurred in mice before the onset of pain. To asses whether delayed pain was partly the result of increased endogenous opioid function, naloxone or naloxone methiodide was administered. Both opioid receptor antagonists led to pain onset 4 weeks earlier than in vehicle- treated mice, indicating a role of the peripheral opioid system in masking OA pain. 17

18. RCT 2 group, 2 phases morphine 1 mg (total 2 mg during study) Follow-up 9 days Pain were assesment NRS, VAS and MPQ 18

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21. Our applies other intraarticular techniques Intra-articular drug injection Intra-articular RFT Genicular nerves RFT 21

22. Target 1 Target 3 Target 2 Genicular nerve of traditional RFT or cooled RFT 22

23. Genicular nerve of traditional RFT or cooled RFT 23

24. Conclusion Intra-articular opioid apply in intraoperative period is useful, Periarticular opioid apply in acute postoperative period is useful, The data of opioids for osteoarthritis knee pain treatment is insufficient, There are needs to long time RCT, There are new therapy modalities in osteoarthritis knee pain 24

25. “Thank you for your attention.” 25