NMDA Receptor Antagonists. Tanyanun Ngam-ek-eu Samita Pirotesak Supervised by Assist.Prof. Nantthasorn Zinboonyahgoon

Transcription

1 NMDA Receptor Antagonists Tanyanun Ngam-ek-eu Samita Pirotesak Supervised by Assist.Prof. Nantthasorn Zinboonyahgoon

2 NMDA Receptor N-metyl-D-aspartic-acid receptors Glutamate-gated cation channels with high calcium permeability Important therapeutic targets for many CNS disorders: neuropathic pain, Parkinson s, Alzheimer s diseases,and mood disorders etc. Blanke ML. Activation Mechanisms of the NMDA Receptor. In: Van Dongen AM, editor. Biology of the NMDA Receptor

3 NMDA receptor

4 NMDA Receptor Antagonists for treatment of postoperative pain Postoperative pain association with sensitization of the central nervous system (CNS) -> elicits pain hypersensitivity NMDA receptor antagonists commonly have been implicated in perioperative pain management Anaesthesiology 2007; 21: 85-98

5 Benefits of NMDA Receptor Antagonists Analgesic synergy and postoperative opioid-sparing effect Anti-hyperalgesic effect related to prevention of postoperative hyperalgesia and tolerance associated with opioid use Patients with opioids tolerance Patients with high risk of developing chronic pain Anaesthesiology 2007; 21: 85-98

6 NMDA Receptor Antagonists Ketamine Magnesium N2O Dextrometrophan Memantine

7 Ketamine A racemic mixture of R-( )- and S-(+)-isomers The S-(+)-isomer is the more potent analgesic (twofold) with a shorter duration of action. Anesthetic dose is 1-2 mg/kg Subanesthetic dose also has analgesic effect An initial infusion rate: mg/kg/h Infusion rates as low as mg/day (run as 4 8 mg/h) in an average adult Macintyre P.Acute Pain Management (2014)

8 Ketamine Used as an adjunct to pain medicine during peri-operative periods The potentiation of opioid-induced analgesia and the opioid-sparing effect Curr Opin Anaesthesiol 2009; 22:

9 Macintyre P.Acute Pain Management (2014)

10 Opioid sparing effect of ketamine Adding ketamine to morphine for patient-controlled analgesia after thoracic surgery results in a significant reduction in cumulative morphine consumption and reduces the likelihood of morphine-induced side effects BJA Continuous Low-Dose of Ketamine Improves the Analgesic Effects of Fentanyl Patient-Controlled Analgesia After Cervical Spine Surgery The ketamine infusion of 2 mg/kg/day (at a serum concentration of ng/ml) enhanced fentanyl PCA-induced postoperative analgesia Anesth Analg 2008; 107:

11 Opioid sparing effect of ketamine Postoperative Ketamine Administration Decreases Morphine Consumption in Major Abdominal Surgery A prospective randomized double-blind controlled study Three groups: (1) INTRA group : ketamine bolus before incision + infusion intraoperatively (2) PERI group : ketamine bolus before incision + infusion intraoperatively and 48hr postoperatively (3) CTRL group (placebo) Anesth Analg 2008; 106:

12 Opioid sparing effect of ketamine Pain score after surgery was lower in PERI group and INTRA group, compared with patients receiving placebo. The morphine-sparing effect was observed only in PERI group Anesth Analg 2008; 106:

13 Anesth Analg 2008; 106:

14 CTRL INTRA PERI Anesth Analg 2008; 106:

15 Ketamine for opioids tolerance Non opioids analgesic Opioids potentiation Opioids sparing Anti-tolerance

16 The mechanism of opioid acute tolerance and preventive effects of ketamine Pretreatment with NMDA receptor antagonists significantly inhibited mu-opioid receptor internalization in neurons caused by laparotomy in guinea pigs It could therefore be predicted that ketamine could inhibit opioid receptor internalization. Indeed, ketamine prevents opioid-induced hyperalgesia and acute tolerance British Journal of Anaesthesia 107 (2): (2011)

17

18 The Effects of Low-Dose Ketamine on Acute Pain in an Emergency Setting: A Systematic Review and Meta-Analysis Eun Nam Lee, Jae Hoon Lee2 1 Department of Nursing, Dong-A University, Daesin Gonwon-Ro, Seo-Gu, Busan, South Korea, 2 Department of Emergency Medicine, Dong-A university College of Medicine, Daesin Gonwon- Ro, SeoGu, Busan, South Korea

19

20 Ketamine vs Placebo Ketamine vs Morphine Ketamine vs Fentanyl

21 Gastrointestinal Neurological Psychological Major cardiopulmonary Minor cardiologic

22 Conclusion: Ketamine alone in acute pain When ketamine was compared to opioids, its effects on analgesia and the reduction of rescue analgesia were similar to those of opioids Ketamine was associated with a greater risk of neurological and psychological events

23 Ketamine for the prevention of postoperative persistent pain The reduction of central sensitization as a result of NMDA receptor antagonists has been shown to be associated with the prevention of development of persistent pain in animal studies The study suggests that ketamine should be administered during the 48 h following surgery and acute pain should be aggressively cared for by multimodal techniques Eur J Pain 2009; 13:

24 A systematic review and meta-analysis of ketamine for the prevention of persistent post-surgical pain E. D. McNicol, R. Schumann and S. Haroutounian Department of Anesthesiology and Pharmacy, Tufts Medical Center, Boston, MA, USA, 2 Department of Anesthesiology, Tufts Medical Center, Boston, MA, USA and 3 Department of Anesthesiology, Washington University in St Louis, St Louis, MO, USA Acta Anaesthesiol Scand 2014; 58:

25 Incidence of PPSP at 3 month Arthoplasty Hemorrhoidectomy Mastectomy Mixed Thoracotomy Acta Anaesthesiol Scand 2014; 58:

26 Incidence of PPSP at 6 month Arthoplasty C-section Colectomy Limb amputation Prostatectomy Thoracotomy Acta Anaesthesiol Scand 2014; 58:

27 Ketamine for prevention of persistent postsurgical pain; conclusion Short-term effects of ketamine on acute pain outcome suggests the efficacy of intravenous ketamine only in comparison with placebo in preventing PPSP at 3 and 6 months No unifying effective regimen has emerged despite the long history of ketamine in clinical practice Ketamine may be appropriate in patients undergoing painful surgeries or who are expected to require large doses of opioids postoperatively Acta Anaesthesiol Scand 2014; 58:

28 Side effect of ketamine Psychotomimetic side effects: dose-dependent include dreaming and nightmares, hallucinations and dysphoria Other adverse effects: nystagmus, blurred vision,nausea and vomiting and diplopia (Laskowski et al., 2011) These side effects may be reduced by the concurrent administration of benzodiazepines Macintyre P.Acute Pain Management (2014)

29 NMDA Receptor Antagonists Ketamine Magnesium Others

30 Magnesium Prevent seizure in preeclampsia patients Treatment of arrhythmia and asthma Potentiate effects of muscle relaxation Anesthetic- and analgesic-sparing effect -> reducing anesthetic requirements Attenuating cardiovascular effects from laryngoscopy and intubation Sang-Hwan Do. Magnesium: a versatile drug for anesthesiologists. Korean J Anesthesiol 2013 July 65(1): 4-8

31 Magnesium- Muscle relaxation muscle fiber excitability amplitude of endplate potential Potentiation of a neuromuscular blockade by nondepolarizing NMBAs Reduce requirements for nondepolarizing NMBAs ACh release Sang-Hwan Do. Magnesium: a versatile drug for anesthesiologists. Korean J Anesthesiol 2013 July 65(1): 4-8

32 Magnesium- Analgesia in surgical patients Enhances the analgesic actions as an adjuvant agent Usual regimens of MgSO4 administration: Loading dose of mg/kg Followed by a maintenance dose of 6-20 mg/kg/h A single bolus of magnesium without maintenance infusion was also effective Sang-Hwan Do. Magnesium: a versatile drug for anesthesiologists. Korean J Anesthesiol 2013 July 65(1): 4-8

33 25 RCTs compared magnesium with placebo Independent of the mode of administration (bolus or continuous infusion) Anaesthesia 2013, 68, 79 90

34 Bolus only Bolus and infusion Infusion only Cumulative intravenous morphine consumption was reduced by an average of 24.4% in favor of the magnesium group at 24 h postoperatively (mean difference: 7.6 mg; 95% CI -9.5 to mg; p < )

35 Gastrointestinal surgery Morphine consumption was reduced by an average of 15% in gastrointestinal surgery (p = 0.02) 12.7% in gynaecological surgery (p < ) 37.9% in orthopaedic surgery (p < ) 33.8% in other types of surgery Gynecological surgery Orthopaedic surgery Other types of surgery Cumulative intravenous morphine consumption at 24 h postoperatively was reduced in all types of surgery

36 Pain score at 24 h at rest Pain score at 24 h on movement Early postop. IV opioid consumption Early postop. pain score at rest Early postop. pain score on movement Time to first analgesic request PONV Mean pain scores at rest and on movement at 24 h postoperatively were reduced by 4.2 (95% CI -6.3, -2.1; p < ) and 9.2 (95% CI -16.1, -2.3; p = 0.009) out of 100, respectively Reduced by an average of 3.6 mg in favor of the magnesium group (95% CI -5.2 to -2.1 mg; p < ) Early postoperative pain scores at rest and on movement were reduced by 6.9 (95% CI -9.6 to -4.2; p < ) and 6.5 (95% CI 10.0 to-.9; p < ) out of 100, respectively No significant differences Pruritus

37 Concluded that Peri-operative intravenous magnesium reduces opioid consumption, and to a lesser extent, pain scores, in the first 24 h postoperatively, without any reported serious adverse effects Anaesthesia 2013, 68, 79 90

38 Magnesium- Considerations Potentiate muscle relaxation Increased sensitivity to both depolarizing and non-depolarizing muscle relaxants Non-depolarizing muscle relaxants: reduced ED50 and onset time, and increased duration of action -> doses should be reduced by 25-50% Total recovery time, determined as time from injection until a train-of four ratio of 0.9, was significantly longer after administration of MgSO4 Susanne Herroeder. Magnesium Essentials for Anes. Anesthesio 2011; 114:971 93

39 Magnesium- Considerations Potentiate muscle relaxation depolarizing agent The clinical effects of MgSO4 seem to be rather small MgSO4 does not interfere with onset and duration of succinylcholineinduced neuromuscular block Seems to prevent associated muscle fasciculations May attenuate potential succinylcholine-induced increases of serum potassium Susanne Herroeder. Magnesium Essentials for Anes. Anesthesio 2011; 114:971 93

40 Magnesium- Considerations Cardiovascular depression by acting as a CCB Inhibition of catecholamine release reduces plasma epinephrine and NE concentrations after endotracheal intubation -> reduces hypertensive responses during anesthesia induction Used with caution in hypovolemic patients and who limited cardiac capacity Slow administration (> 10 min) of the loading dose of MgSO4 may minimize cardiovascular side effects Sang-Hwan Do. Magnesium: a versatile drug for anesthesiologists. Korean J Anesthesiol 2013 July 65(1): 4-8

41 Magnesium- Considerations Incidence of bradycardia was higher in the Mg group, without increased hypotension Sedation scores were similar in both groups Measured serum Mg levels were higher in the magnesium groups compared to placebo groups Anaesthesia 2013, 68, 79 90

42 NMDA Receptor Antagonists Ketamine Magnesium Others : Nitrous oxide, Dextromethorphan, Memantine

43 Nitrous oxide Analgesic effect -> opioid in nature Anxiolytic effect -> resembles benzodiazepines may be initiated at selected subunits of GABA-A receptor Anesthetic effect may involve actions at GABA-A receptors and possibly at N-methyl-D-aspartate receptors Subanesthetic concentrations of N2O produce only analgesic and anxiolytic effects Dimitris E. Emmanouil. Advances in Understanding the Actions of Nitrous Oxide. Anesth Prog 2007; 54:9 18

44 Perioperative nitrous oxide may have a role in preventing chronic pain after surgery This large multicenter trial evaluated patients 1 y after surgery using structured telephone interviews 12% of patients experienced chronic pain, with or without nitrous oxide Overall, nitrous oxide administration had no effect on the development of chronic pain, 12 months after surgery

45 In a subgroup of Asian patients 30% decrease in the risk of chronic postsurgical pain with nitrous oxide Nitrous oxide reduced chronic pain risk, dependent on genotype

46 Dextromethorphan

47 Dextromethorphan Low-affinity noncompetitive NMDA receptor antagonist Perioperatively use could potentially provide similar benefits to preemptive ketamine therapy in a simple oral, intramuscular, or IV formulation Dosage recommendation : mg oral one dose before surgery Michael R.King. Perioperative Dextromethorphan as an Adjunct for Postoperative Pain, A Meta-analysis of RCT. Anesthesiology 2016; 124:

48 Dextromethorphan Forest plot for total opioid use over h favor dextromethorphan group with difference in means Michael R.King. Perioperative Dextromethorphan as an Adjunct for Postoperative Pain, A Meta-analysis of RCT. Anesthesiology 2016; 124:

49 Dextromethorphan : Pain scores 1 h postoperatively 4-6 h postoperatively 24 h postoperatively A Meta-analysis of RCT. Anesthesiology 2016; 124:

50 Dextromethorphan This meta-analysis suggests that dextromethophan Reduce morphine requirements 24 to 48 h after surgery Reduce pain from 1 to 24 h postoperatively Anesthesiology 2016; 124:

51 Dextromethorphan: side effects Both opioids and dextromethorphan primarily consist of nausea, vomiting, dizziness, and lightheadedness For dextromethorphan side effects and concerns include dose-related tachycardia, respiratory depression, gastrointestinal symptoms, and abuse potential Michael R.King. Perioperative Dextromethorphan as an Adjunct for Postoperative Pain, A Meta-analysis of RCT. Anesthesiology 2016; 124:

52 Memantine

53 Memantine Memantine is an oral NMDA antagonists Safe and well-tolerated Some studies have shown that memantine is able to prevent postoperative pain if administered prior to nerve injuries P. Rahimzadeh. A Comparative Study on the Efficacy of Oral Memantine and Placebo for Acute Postoperative Pain in Patients Undergoing DCR. Anesth Pain Med June; 7(3):e45297

54 Memantine Memantine was administered at a dose of 5 to 20 mg daily after mastectomy for two weeks The study showed that postoperative pain significantly decreased in patients who received memantine compared with the control group Morel V et al. Memantine before Mastectomy Prevents Post-Surgery Pain: A Randomized, Blinded Clinical Trial in Surgical Patients. PLoS One. 2016;11(4):e The oral single-dose 20 mg of memantine administered before DCR can reduce postoperative pain compared with placebo Anesth Pain Med June; 7(3):e45297

55 Memantine Some studies also obtained results inconsistent with those of our study concerning the effect of memantine on reducing pain In a systematic review study, Collins et al. suggested that there is insufficient evidence regarding the effectiveness of NMDA receptor antagonists on neuropathic pain P. Rahimzadeh. A Comparative Study on the Efficacy of Oral Memantine and Placebo for Acute Postoperative Pain in Patients Undergoing DCR. Anesth Pain Med June; 7(3):e45297

56 Take home massage NMDA receptor antagonists benefit in patients with opioids tolerance and patients with high risk of developing chronic pain Ketamine: effects may beyond pharmacologic duration, use low dose but regimen still inconclusive Mg: opioid sparing effects and reduce pain score, but caution in neuromuscular and cardiovascular effects Other NMDA receptor antagonists may have opioid sparing effects but long term outcome still inconclusive

57 THANK YOU