1. Effect of postoperative pain therapy on surgical outcome Prof. Dr. sc. Višnja Majerić Kogler Department for Anaesthesiology, Reanimathology and Intensive KBC Zagreb

2. Intense nociceptive somatic,visceral and neuropathic post-surgical pain has in the last years been considered the most important factor of development of endocrine and nerohumoral disorders in the immediate postoperative period. The overall effects of postoperative pain treatment on outcome remains debatable Kehlet H, Holte K Br J Anaesth 2002.

3. Effective pain treatment is not only a part of multimodal rehabilitation process, but also a necessary condition for applying most of the other postoperative measures. Thus postoperative pain treatment may significantly change postoperative outcome

4. Corner stones of analgesic strategies Patient-controlled administration of i.v. opioids Peripheral and central nerve blocks using local anaesthetic agents, The latter being considered more effective than the former Nevertheless,each technique has its own limitations and none can achieve complete postoperative pain control.

5. Outline Could postoperative pain treatment modified stress response? Is postoperative pain treatment effective? Can we avoid postoperative side-effects of analgesic agents? Does postoperative pain treatment decrease hospital stay and the incidence of postoperative complications? Does postoperative pain treatment prevent the occurrence of postoperative chronic pain syndrome?

6. Pain relief may be a powerful technique to modifay surgical stress response Hewever there is a pronounced differential effect of the various postoperative pain – relieving technique on surgical stres response Kehlet 1998

7. TREATMENT OF POSTOPERATIVE PAIN ↓ THE STRESS RESPONSE IS A COMPLEX PROCESS Conventional analgesics: opiates and opiate-like drugs, NSAIDS, COX2 inhibitors, ketamine, and paracetamol all have no significant effects on reducing the stress response in comparison to nerve block techniques Kehlet, Holte 2002.

8. CONTINUOUS EPIDURAL ANALGESIA Strong suppressor of stress endocrine secretion Catabolic suppressor Decreases intestinal obstruction Provides optimal conditions for post operative recovery Kehlet Holte 2001,

9. Table 1 Effects of analgesic techniques on postoperative surgical stress Responses (adapted from reference 40). = no effect;  =small effect;  =moderate effect;  =major effect Type of analgesia Endocrine- Inflammatory metabolic responses responses Systemic opioid (PCA or intermittent)  NSAID   Epidural opioid  Lumbar epidural local anaesthetics  (lower extremity surgery) Thoracic epidural local anaesthetics  (abdominal surgery)

10. Is postoperative pain treatment effective? No true general consensus exists for optimal medications and techniques for individual painful procedures The studies were designed to include only pain treatment, isolated from other factors which could influence the result of post surgical treatment

11. General principals Multimodal balanced analgesia and techniques “opioid sparing” Surgery Specific (Tailored) Use of regional analgesia techniques for large surgical procedures incorporates the “fast track” concept of multimodal rehabilitation

12. EPIDURAL ANALGESIA Continuous infusion of local anesthetics and opioids Safe and effective way of reducing dynamic pain, following thoracic and upper abdominal surgery Jorgensen 2001

13. Copyright restrictions may apply. Block, B. M. et al. JAMA 2003;290:2455-2463. Mean VAS Pain Scores by Postoperative Day

14. Safety and efficasy of patient-controlled analgesia. Macintyre P. E. British J Anaesthesia 2001. This review will consider: Analgesic efficacy Patient outcome – satisfaction, morbidity Patient factors that may affect safety and efficacy Equipment factors The PCA prescription Medical and nursing staff factors

15. PCA can be a very effective and safe method of pain relief and may allow easier individualization of therapy compared with conventional methods of opioid analgesia. However it is not a “ one size fits all” or a “ set and forget” therapy and original prescriptions may need to be adjasted if maximal benefits is to be given to all patients. However, in many busy hospital wards, staff numbers, time, attitudes, and knowledge may serve to limit the efficasy of nurse-administered pain relief. It is therefor likely that the popularity of PCA will continue and that PCA will remain a commonly used method of analgesia.

16. PCA The general belief seems to be that patients satisfaction is improved The greater analgesic efficasy without increase in side effects The overall negative outcome effects by PCA correspond well with minor effects on postoperative dynamic pain, stress respons and organ dysfunction The lenth of hospital stay is not reduced Walder B 2001, Kehlet H 2005.

17. The regional catheter technique - advantages Meta analysis of 45 RCS with 205 patients 5 abdominal, 13 cardiothoracic, 6 ginecologic, 12 orthopaedic studies Continuous wound catheter techniques Reduced pain scores 32% Opioids consumption 25% Decreased postoperative nausea and vomiting 30% Increase in patients satisfaction Ranta PO 2006, Richman JM 2006.

18. Dolin S. et al. Effectiveness of acute postoperative pain management: Evidence from published data.British Journal of Anaesthesia 2002;89:409-23. Aim of the study: To investigate incidence of moderate to severe pain after major surgery – abdominal, major gynaecological, orthopedic, thoracic Analgesic technique: IM, PCA, epidural Shortest observational period 24h Pain intensity results were obtained from 19.909 patients Pain relief results from 9.068 patients

19. Moderate to severe pain at rest

20. Moderate to severe pain on movement

21. Severe pain

22. Effectiveness of pain management Conclusions: Severe pain and poor of fair pain relief was expirienced by almost 1 in five patients. The audit commision in the UK has proposed a standard that less of 5% of patients should experience severe pain after surgery by 2002. This review suggests that achieving that standard will be difficult.

23. Can we avoid postoperative side-effects of analgesic agents? Especially in case of opioids Side-effects: respiratory depression (rare), nausea, vomiting, pruritus, urinary retention, prolongation of postoperative ileus (frequent) These side-effects have significant impact on hospital stay Morphine side-effects are related to morphine dose Reduce dosage in order to decrease side-effects

24. Multimodal Analgesia – A Worthy Working Hypothesis Kehlet 1999 “opioid sparing” technique NSAID and COX2 Romsing, Moiniche 2004 Acetaminophen Romsing 2002 Ketamin Elia, Tramer 2005 Gabapentin, Pregabalin Dahl 2004 20 – 40% decreases the use of opioids

25. Effects of NSAID on PCA Morphine Side Effects; Meta analysis of RCT Anesthesiology 2005. Marret et al. Twenty –two prospective randomized double- blind studies including 2307 patients were selected. NSAIDs decresed significantly postoperative nausea and vomiting by 30%, nausea alone by 12%, vomiting alone by 32% and sedation by 29%. A regression analysis yielded findings indicating that morphine consumption was positively correlated with the incidence of nausea and vomiting. Pruritus, urinary retention, and respiratory depression were not significantly decreased by NSAID.

26. Can we avoid postoperative side-effects of analgesic agents? Non-opioid agents have its own side-effects: NSAID – GI hemorrhage, COXib – CV complications Epidural analgesia has its own side-effects: hypotention, parasthesia, muscle weakness, urinary retention Dilute the concentration of solution but not too diluted. It mail fail to achieve pain relief

27. Does postoperative pain treatment decrease hospital stay and the incidence of postoperative complications? This is the most controversial issue Most of the literature concerning this problem is dedicated to the effect of epidural analgesia

28. Epidural anaesthesia and analgesia and outcome of major surgery : a randomised trial. Rigg J RA et al.Lancet 2002;359:1276-82.

29. Aim of the study: to compare adverse outcomes in in hight risk patients managed major surgery with epidural block or alternative analgesic regiments with general anaesthesia The primary endpoin twas death at 30 days or major postsurgical morbidity Conclusion: Most adverse morbid outcomes in high – risk patients undergoing major abdominal surgery are not reduced by use of combined epidural and general anaesthesia and postoperative epidural analgesia. However this technique improve analesia effect, reduce the respiratory failure and serious adverse effects

30. Other authors have collected evidence supporting the use of central blocks of local anaesthetic to decrease the incidence of postoperative pulmonary complications compared with the use of systemic opioids. The incidence of postoperative myocardial infarction has been shown to be lowered by the use of thoracic epidural anaesthesia and analgesia Meissner A, Rolf N, Van Aken H. Thoracic epidural anesthesia and the patient with heart disease: benefits, risks, and controversies. Anesth Analg 1997; 85: 517–28

31. Cardiac surgery The benefits of thoracic epidural anaesthesia include a decrease in the risk of dysrhythmias and pulmonary complications, and a reduction in the time to tracheal intubation, but no statistically significant improvement in the incidence of myocardial infarction and mortality has been demonstrated. However,in these circumstances, all benefits are outweighed by the risk of epidural haematoma related to full anticoagulation that is estimated to approximate 1/1500 patients. Liu SS, Block BM, Wu CL. Anesthesiology 2004 Ho AM, Chung DC, Joynt GM. Chest 2000.

32. Does postoperative pain treatment prevent the occurrence of postoperative chronic pain syndromes?

33. Estimated incidence Persistent Postsurgical Pain: risk factors and prevention The Lancet, Volume 367, Issue 9522, 13-19 May 2006, Pages 1618-1625 Henrik Kehlet, Troels S Jensen, Clifford J Woolf

34. Persistent Postsurgical Pain the consequence either of ongoing inflammation or, much more commonly, a manifestation of neuropathic pain, resulting from surgical injury to major peripheral nerves Persistent Postsurgical Pain: risk factors and prevention The Lancet, Volume 367, Issue 9522, 13-19 May 2006, Pages 1618-1625 Henrik Kehlet, Troels S Jensen, Clifford J Woolf

35. CLINICAL INVESTIGATIONS De Kock et al. 2001., 2005. Demonstrated that, the area of hyperalgesia – one measure of central sensitisation – could perhaps predict patients likely to develop persistent pain after surgery

37. PRE – EMPTIVE ANALGESIA TWO METHODS Conduction blocade with local anesthetics Suppression of the excitability of the nervous system before it receives the nociceptive input Many trials evaluating preemptive analgesia have been conducted in patients undergoing elective surgery, but the results have been inconclusive

38. In a prospective randomised trial Senturk 2002.compared the effect of three different analgesia techniques in 69 thoracotomy patients. Two groups recived thoracic epidural analgesia: Pre TEA - post TEA bupivacain, morphin The third group iv PCA with morphin Pre- TEA significantly less pain postoperativaly Lower incidence of pain after six months 45% : 78%

39. Reuben SS, Makari Judson G., Laurie SD.2006.Evaluation of efficacy of the perioperative administration of venlafaxine XR in the prevention of postmastectomy pain syndrome. J Pian Symptom Manage 27:133-39 FASSOULAKI A, TRIGA A MELEMENI A et al 2005 Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Anesth Analg 101:1427-32

40. Is postoperative pain treatment effective?

41. Three and 6 months after surgery, 18 of 22 (82%) and 12 of 21 (57%) of the controls reported chronic pain versus 10 of 22 (45%) and 6 of 20 (30%) in the treatment group (P 0.028 and P 0.424, respectively); 5 of 22 and 4 of 21 of the controls required analgesics versus 0 of 22 and 0 of 20 of those treated (P 0.048 and P 0.107, respectively). Multimodal analgesia reduced acute and chronic pain after breast surgery for cancer.

42. Strategies In thoracic surgery, epidural analgesia, compared to iv PCA morphine, tends to decrease the incidence of chronic pain syndrome.  control of acute pain Activation of NMDA receptors  Post-operative administration of low-dose Ketamine (0.1~0.5 mg/kg)  decrease opioid consumption  decrease the incidence of chronic pain syndrome several months after surgery

43. Strategies : Gabapentin Gabapentin  suppression of sodium channels, calcium channels and glutamate receptor activity at peripheral, spinal and supraspinal sites  reduce consumption of opioid postoperatively Promising results in reduction of chronic pain have been obtained in breast surgery with Gabapentin.

44. Other agents with potential Prostaglandins  COXibs Local anaesthetic agents: ropivacaine, EMLA … α 2 - adrenergic agents Tricyclic antidepressant: venlafaxine

45. Multimodal fast-track rehabilitation and outcome – future research Future research should focus on: Combination of several techniques such as continuous periferal nerv block, continuous wound infusion of local anaesthetics, NSAID s/COX2 inhibitors, paracetamol, α -2 agonists, ketamin, Dextromethorphane, gabapentin/pregabalin Glucocorticoids e.t.c.

46. Each medication and technique component alredy has been demonstrated to provide analgesia and opioid sparing, but multiple combination to enhance analgesia, reduce stress response and dynamic pain and prevent chronic pain are required The concept of a multimodal postoperative rehabilitation programme in which pain relief is the key factor is a major task for the future