Effective post-operative analgesia. (Educational Review)

Cooper JG, Haetzman M, Stickle BR

Keywords: post-operative analgesia, acute pain, multimodal or balanced analgesia.

Abstract

Effective treatment of acute pain should be high on the agenda of all staff looking after post-operative patients. Often, pain control after surgery can be less than optimal. The reasons for this are multifactorial but include staffing and resource issues, over reliance on single analgesic agent regimens, under-estimation of effective dosages, over estimation of analgesic duration of action and misconceptions about particular side-effects and the potential for addiction.

This article explores some of the issues surrounding the provision of post-operative analgesia and describes the principles for achieving effective pain relief whilst minimising interference with healing and recovery. The authors recommend a balanced or multimodal approach to the provision of analgesia in the post-operative setting.

Introduction

The relief of pain and suffering is, and always has been, one of the primary aims of Medicine. In the sphere of palliative medicine, where the main goals are patient comfort and symptom control, great attention is paid to analgesia. However, attitudes to the control of post-operative pain can be somewhat different. Acute pain may be viewed as a benign self-limiting condition, a side effect of disease or the treatment thereof. Management of post-operative pain may have little or no effect on the patient's eventual outcome and may sometimes be perceived as interfering with the optimal assessment and management of surgical pathology. This article seeks to explore some of the issues surrounding the provision of post-operative analgesia, the benefits and drawbacks of different techniques and to establish the principles for achieving effective analgesia following surgery whilst minimising interference with the processes of healing and recovery in the post-operative period.

Benefits of post-operative analgesia

Post-operative pain is an unpleasant experience for the patient but it is also associated with a number of physiological responses that are thought to contribute to organ dysfunction and postoperative morbidity. Although good post-operative analgesia is associated with less post-operative physiological derangement, an improvement in post-operative morbidity cannot always be demonstrated.1,2

Systemic opioid administration can provide good analgesia post-operatively. Patient controlled analgesia (PCA) is associated with greater analgesic efficacy than intramuscular dosing and high levels of patient satisfaction however there is no evidence of any influence on postoperative outcome.3 Similarly, non-steroidal anti-inflammatory drugs have not been shown to improve postoperative outcome and have no appreciable effect on the surgical stress response.4

Epidural anaesthesia, however, is associated with attenuation of the surgical stress response2,4 and there is evidence to support an associated reduction in post-operative morbidity and mortality.5 Epidural analgesia in the post-operative period is associated with a reduced incidence of myocardial ischaemia and dysrhythmias when compared with systemic opioids.6 A statistically significant reduction in cardiac morbidity has been demonstrated in high-risk patients undergoing major surgery.7,8 A reduction in post-operative pulmonary complications has also been demonstrated.9,10 Epidural analgesia has been shown to reduce the incidence of thrombosis of vascular grafts8 and review points to a reduction in the incidence of deep venous thrombosis a variety of operations.2 When compared to parenteral analgesia, there is a significantly lower incidence of infection when postoperative epidural analgesia is used.7,8 A reduction in the duration of post-operative ileus has also been demonstrated when post-operative analgesia is provided by epidural local anaesthetic rather than systemic opioids.2

Post-operative pain management: is there a problem?

Although there have been great advances in the field of pain management with a greater number of analgesic agents and techniques available, studies show that a significant number of patients still experience moderate or severe pain post-operatively. A review of pain control in 1985 suggested that 41-75% of patients experienced moderate to severe pain post-operatively.11 The same survey demonstrated that 56% of nurses gave less than six doses of intramuscular opioid post-operatively and that the majority of nurses did not give analgesia until the patient complained of pain.11 In 1994 a study conducted in a university hospital in the United Kingdom found that moderate pain was experienced by 25.2% of patients post-operatively and 9.2% of patients experienced severe pain.12 In a 1995 survey of acute pain management in U.S hospitals 77% of adult patients reported pain after surgery with 80% of these experiencing moderate to extreme pain.13 Clearly, in a large number of cases, post-operative pain management is inadequate.

Barriers to the delivery of good analgesia

Poor post-operative pain management occurs for a number of reasons. Over reliance on intramuscular opioids in many institutions may be a contributory factor. A survey of acute pain services in the UK in 1995 found that, in virtually all hospitals surveyed, techniques such as patient controlled analgesia and epidural opioids were being used. However, in 42% of hospitals these techniques were used in less than 10% of patients undergoing major surgery. The administration of intramuscular opioids was the most commonly used analgesic technique with 47% of hospitals using it in more than 50% of patients.14

Intramuscular opioids can provide effective analgesia but only if administered in the appropriate dose at appropriate intervals. Gould et al.15 found that a considerable improvement in post-operative pain could be achieved by regular pain assessment and the more frequent administration of intramuscular opioid guided by an algorithm. However, in clinical practice this may be difficult to achieve. In a recent review of published trials16 comparing intramuscular analgesia with PCA and epidural analgesia, intermittent intramuscular analgesia was associated with the highest incidence of moderate (67.2%) and severe (29.1%) pain. The failure of intermittent intramuscular analgesia may be related to the fact that although analgesics are prescribed they are not always given. Researchers have found that patients experiencing severe pain may have received as little as 26-36% of their prescribed analgesia.12,17 Personal experience suggests that these problems are most strongly related to ward nurse staffing levels and workload though medical and nursing staff attitudes and education undoubtedly contribute too.

Pleasingly, there is some evidence that this situation may be improving. A recent study of epidural analgesia following upper abdominal surgery found that, in 67% of hospitals surveyed, this technique was used frequently and that epidural analgesia was considered to be the best mode of analgesia available by 80% of respondents.18 However, the use of epidural analgesia is not without its problems.19 There is, at present, a significant failure rate associated with the use of this technique with approximately 21% of patients not receiving adequate analgesia.16

Most commonly it is the staff looking after the surgical patient who control the analgesia he or she is given. Their attitudes and prescribing practices may be the most important factors in deciding the analgesia an individual receives. Misconceptions and fears regarding certain analgesics can result in under-treatment of pain in the post-operative setting. With opiates especially, there are exaggerated fears regarding their potential for side effects and addiction. This, coupled with underestimation of pain and an over estimation of opioid half-life leads to their being prescribed in inadequate doses.17 Non-Steroidal Anti Inflammatory Drugs (NSAIDs) also engender concerns regarding their side-effects, particularly those relating to renal function, gastro-intestinal bleeding, platelet function and more recently bone healing. These often unnecessarily restrict their use in post-operative surgical patients. Concern regarding the possible masking of important clinical signs by potent analgesics can lead to delay in the administration of these drugs. Evidence suggests that these fears are unfounded and that analgesia often assists effective examination.20

Staffing levels on wards can influence the provision of analgesia. It may be that prescribed analgesics can only effectively be offered during formal drug rounds. Post-operative patients frequently complain of difficulties in obtaining medicines prescribed on an 'as required' basis promptly and at sufficient frequency to effectively alleviate pain. In such circumstances it is useful to prescribe drugs on a regular rather than as required basis so that a background level of pain relief can be established rather than a patient having to request analgesia when pain becomes more pronounced.

The advent of multidisciplinary pain teams has led to improved delivery of analgesia and has also taken on an important educational role with regards ward staff.

Balanced analgesia

The adverse effects of opioids and the advent of ambulatory surgery with rapid rehabilitation has led to a reappraisal of post-operative pain management and a shift away from reliance on powerful opioids as the sole post-operative analgesic. From this has emerged the concept of 'multimodal' or 'balanced' analgesia21 where opioids are used in conjunction with non-opioid analgesics to reduce the amount of opioid required (and therefore related side effects) whilst maintaining good analgesia. Pain control can be excellent using multimodal analgesia but disappointingly, so far there has been no overall effect on morbidity and mortality.4,22

Methods of Analgesia

Opioids

Opioids given by the intravenous (IV) route provide rapid and predictable pain control when compared with intramuscular (IM) administration. In the post-operative period the systemic absorption of IM morphine may be variable due to hypothermia, hypovolaemia and peripheral vasoconstriction. If not precluded, opioids can be given effectively by the subcutaneous or oral route.

Opioids are predominantly inactivated in the liver with metabolites excreted in the bile and urine. Care must be exercised in patients with renal impairment to avoid the accumulation of active metabolites such as morphine-6-glucuronide. Opioids act against dull, poorly localised pain resulting from stimulation of supraspinal and spinal pathways. Not all types of pain are equally sensitive to opioids and it is important to recognise at the outset that opioids may frequently fail to control pain associated with movement.

Morphine, diamorphine, pethidine and fentanyl are commonly used opioids in the management of post-operative pain in this country. Other desirable effects are sedation and anxiolysis. Adverse effects include bradycardia, hypotension and vasodilatation due to reduced sympathetic drive, histamine release and specific vagal effects. GI complications include delayed gastric emptying, increased smooth muscle tone and reduced peristalsis leading to constipation and contraction of the gallbladder and sphincter of Oddi. Pethidine has an atropine like effect that is said to counteract the opioid effect on smooth muscle but this has not been proven clinically. Nausea and vomiting, caused by dopamine (DA) and serotonin (5-HT3) receptor stimulation in the chemo-receptor trigger zone can be problematic for the patient. Respiratory depression due to opioids is a dose dependent phenomenon where the depth and rate of breathing are reduced as a result of decreased sensitivity of the respiratory centre to carbon dioxide. These effects can be reversed by opioid antagonists such as naloxone though it must be appreciated that, in addition to reversing unwanted effects, analgesia will also be reversed. The half-life of naloxone is shorter than many opioids and therefore adverse effects may recur. Careful monitoring of the patient is required and repeat dosing with naloxone may be necessary.

PCA

PCA allows the patient to self-administer small doses of intravenous opioid at frequent intervals, providing better post-op pain relief than intermittent IM injections. PCA allows for variations in opioid requirement as a result of tolerance, variability in pharmocokinetics and changes in pain intensity. To use PCA effectively, the patient must grasp its concept and retain the instructions into the post-operative period. PCA can be used in children who understand how it works. In the elderly the failure rate of PCA increases, perhaps secondary to the increased incidence of post-operative confusional states in this group.

PCA orders should not be deemed routine even though most people do very well with standard instructions. There should be careful assessment of the patients age, cognitive function, drug history, co-morbidity etc. and the proposed surgical procedure prior to prescription of the PCA. Post-operatively there should be regular evaluation of the effectiveness of PCA and orders changed as appropriate.

Additional prescription of oxygen, anti-emetics and opioid antagonists should be clear, as should the prohibition of further opioid administration.

In this country morphine is by far the most common opioid used in PCA and is typically given in a 1-2mg bolus giving rapid onset of analgesia. PCA is designed to maintain and not establish analgesia and should be used administration of a loading dose of opioid given in theatre or in the recovery room. The bolus dose is designed to raise the serum concentration to a level above the minimum effective analgesic concentration (MEAC) but not to such a degree as side effects occur. Ideally this bolus dose would provide good analgesia for 30-60 minutes before an additional dose is required. The lockout period after the administration of a bolus of morphine is usually in the order of five to ten minutes. Background infusions can be prescribed in an attempt to maintain an effective analgesic concentration for a longer time between bolus doses. However, the literature suggests that analgesia is not altered and side effects are increased.23,24,25 Their routine use is therefore discouraged and is usually limited to those with very high opioid requirements often due to preoperative tolerance.

Tramadol

Tramadol is a synthetic analgesic that is a weak opioid receptor agonist. It also exerts analgesia via the inhibition of noradrenaline and serotonin reuptake and increases the release of 5-HT to modify nociceptive transmission through the activation of inhibitory descending pathways in the CNS. Though it can cause nausea, tramadol is an analgesic that causes minimal sedation, respiratory depression and GI stasis. Tramadol is expensive but can produce effective analgesia even after major surgery.26

Paracetamol

Paracetamol has an important role in balanced analgesia. In adults the regular prescription of paracetamol has been shown to have a significant opioid-sparing effect in post-operative patients,27 typically of the order of 20-30% .28

Paracetamol is often prescribed in combination with codeine. Interestingly, a meta-analysis of trial data demonstrated that at least 60mg of codeine had to be added to 600mg or 650mg of paracetamol to provide worthwhile additional analgesia.29 There is no proven benefit in the addition of dextropropoxyphene to paracetamol.30

Paracetamol is well absorbed orally but can also be given rectally. Rectal absorption is both slower and reduced and increased doses are required.31

Paracetamol is for the most part used as an adjunct in the management post-operative pain and evidence suggests that it is a weaker analgesic than NSAIDS.32 Paracetamol given in combination with NSAIDS has additional benefit33 and it can be used when NSAIDs are contraindicated.

Non Steroidal Anti-Inflammatory Drugs (NSAIDS)

NSAIDS are a heterogeneous class of drugs that exert their anti-inflammatory effects through the inhibition of cyclo-oxygenase (COX) and hence reduce the production of inflammatory prostaglandins (PG). NSAIDS are generally considered to be inadequate as sole agents in the control of immediate post-operative pain,34 but in conjunction with opioids work synergistically and have a significant opioid sparing effect.35

They are free from the sedation and respiratory depression associated with opioids and are particularly useful in the management of pain associated with minor procedures and ambulatory surgery, often obviating the need for opioids. However, the effects of PG inhibition are not restricted to inflamed tissue and this explains why their use is often limited.

The efficacy of different types of NSAID appears to be fairly similar although they do have marked differences in their side-effect profiles, ibuprofen being the most favourable. NSAIDS can be given orally, rectally and more recently parenterally.

There are four principle adverse effects associated with NSAIDS:

1. Loss of PG mediated cytoprotection in gut resulting in gastrointestinal ulceration.

2. Renal PGs are important in the maintenance of renal blood flow and glomerular filtration when blood flow is borderline and therefore the use of NSAIDS can precipitate renal dysfunction in susceptible patients and should be used judiciously in the elderly, those on ACE inhibitors and in the presence of hypovolaemia, dehydration and hypotension.

3. NSAIDS increase the prostacyclin:TXA2 ratio leading to abnormal platelet function that may impair haemostasis.

4. Aspirin-induced asthma: COX inhibition leads to increased levels of arachidonic acid and increased metabolism through the alternative lipoxygenase pathway to form an abundance of leukotrienes which can mediate bronchoconstriction and anaphylaxis. This is only a problem in a small percentage of asthmatic patients and a good history often reveals whether or not the patient has trouble with NSAIDS.

NSAIDs are therefore contraindicated in patients with peptic ulcer disease, renal impairment, aspirin-induced asthma and coagulation defects.

COX 2 inhibitors

COX-2 is an inducible form of cyclo-oxygenase that can be produced in response to a variety of different stimuli e.g. surgical trauma, hypoxia, interleukin-1 and endotoxin. COX-1 is constitutively expressed and is believed to be responsible for normal physiological prostaglandin production involved in cytoprotection of the gut mucosa and in renal tubular function. Thus agents which act on the enzyme induced by tissue damage (COX-2) and spare the protective COX-1 enzyme should have an improved safety profile.36 Studies have shown a reduction in gastrointestinal side effects when compared with conventional NSAIDS although their use in the post-operative setting has yet to be fully evaluated.

Local anaesthetics

Local anaesthetics can be used in a variety of ways to provide analgesia in the post-operative period from wound infiltration to administration via an epidural catheter.

Local anaesthetics act on sodium channels to inhibit transmission of impulses along peripheral nerves but all excitable tissues can be affected and if sufficient amounts enter the circulation toxic effects will be seen.

Epidural

Epidural analgesia is produced by the administration of appropriate drugs into the epidural space just outside the dural sac usually via an indwelling catheter. Local anaesthetic, opioid or a combination of both can be used to provide epidural analgesia. It remains controversial whether epidural administration of opioids alone provides better analgesia than parenteral Opioids (given via PCA).37 However, the combination of local anaesthetic and opioid given epidurally results in synergistic analgesia that is superior to either alone though only when pain was assessed during patient movement and not at rest. This allows improved mobilisation and activity and earlier return to normal functioning which should be the aim of post-operative analgesia.21 Adverse effects depend on the drug used. Epidural local anaesthetic produces sensory, motor and sympathetic blockade. Hypotension, motor block and urinary retention are the major adverse effects associated with this technique. The administration of epidural opioids can be associated with nausea, somnolence, pruritis and respiratory depression.

Nerve blocks

Peripheral nerve blocks such as the ilioinguinal block for hernia repair are relatively easy to perform and can provide effective post-operative pain relief. Peripheral nerve blocks can be used alone or more commonly in conjunction with other analgesics as part of a balanced analgesic technique.

Local anaesthetic infiltration

This is simple, safe and attractive. Many studies have shown the benefit of local anaesthetic wound infiltration in minor surgical procedures 38,39,40 in terms of improved analgesia, better pain scores and reduced opioid consumption when compared with placebo. Long acting local anaesthetics are preferred e.g. bupivacaine since they produce longer analgesia. In contrast, studies involving major abdominal surgery 41,42,43,44,45 demonstrate minimal, if any, benefit over placebo. Some have suggested that it is important to administer the local anaesthetic pre-incision (pre-emptive analgesia) in order to achieve the greatest benefit. Studies performed to demonstrate this effect have produced mixed results. 46,47,48,49

Conclusions

The relationship between good quality analgesia and improved surgical outcome has not yet been conclusively demonstrated. Indeed it may not exist. However the relief of pain and suffering are fundamental aspects of patient care and if we are to improve post operative pain management we should treat this subject seriously and give to it the time and energy it deserves.

References

1. Kehlet H. Surgical stress: the role of pain and analgesia. Br J Anaesth. 1989;63(2):189-195.
2. Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia. Their role in post operative outcome. Anesthesiology. 1995;82(6):1474-1506.
3. Ballantyne JC, Carr DB, Chalmers TC, Dear KBG, Angelillo IF, Mosteller F. Postoperative patient-controlled analgesia : Meta-analyses of initial randomized controlled trials. J Clin Anesth. 1993;5:182-193.
4. Kehlet H. General outcome improvement overview. Regional Anesthesia. 1996;21(6S):5-8.
5. Rodgers A, Walker N, Schug S, McKee A, Kehlet H, van Zundert A, Sage D, Futter M, Saville G, Clark T, MacMahon S. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ. 2000;321:1493-7.
6. Beattie WS, Buckley DN, Forrest JB. Epidural morphine reduces the risk of post-operative myocardial ischaemia in patients with cardiac risk factors. Can J Anaesth. 1993;40(6):532-541.
7. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology. 1987;66:729-736.
8. Tuman KJ, McCarthy RJ, March RJ, DeLaria GA, Patel RV, Ivankovich AD. Effects of epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg. 1991;73:696-704.
9. Ballantyne JC, Carr DB, deFerranti S, Suarez T, Lau J, Chalmers T, Angelillo IF, Mosteller F. The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized controlled trials. Anesth Analg. 1998;86:598-612.
10. Rigg JR, Jamrozik K, Myles PS, Silbert BS, Peyton PJ, Parsons RW, Collins KS. The MASTER Anaesthesia Trial Study Group. Epidural anaesthesia and analgesia and outcome from major surgery: a randomised trial. Lancet. 2002;359:1276-82.
11. Cartwright PD. Pain control after surgery: a survey of current practice. Annals of the Royal College of Surgeons of England. 1985;67:13-16.
12. Oates JDL, Snowdon SL, Jayson DWH. Failure of pain relief after surgery. Attitudes of ward staff and patients to postoperative analgesia. Anaesthesia. 1994;49:755-758.
13. Warfield CA, Kahn CH. Acute pain management programs in U.S. hospitals and experiences and attitudes among U.S. patients. Anesthesiology. 1995;83:1090-1094.
14. Harmer M, Davies KA, Lunn JN. A survey of acute pain services in the United Kingdom. BMJ. 1995;311:360-361.
15. Gould TH, Crosby DL, Harmer M, Lloyd SM, Lunn JN, Rees GAD, Roberts DE, Webster JA. Policy for controlling pain after surgery: effect of sequential changes in management. BMJ. 1992;305:1187-1193.
16. Dolin SJ, Cashman JN, Bland, JM. Effectiveness of acute postoperative pain management: I. Evidence from published data. Br J Anaesth. 2002;89(3):409
17. Marks RM, Sachar EJ. Under treatment of medical inpatients with narcotic analgesics. Ann Intern Med. 1973;78(2):173-181.
18. Cook TM, Eaton JM, Goodwin APL. Epidural analgesia following upper abdominal surgery: United Kingdom practice. Acta Anaesthesiol Scand 1997;41:18-24.
19. Burstal R, Wegener F, Hayes C, Lantry G. Epidural analgesia: Prospective audit of 1062 patients. Anaesth Intens Care. 1998;26(2):165-172.
20. Brewster GS, Herbert ME, Hoffman JR. Medical myth. Analgesia should not be given to patients with an acute abdomen because it obscures the diagnosis. West J Med. 2000;172(3):209-10.
21. Kehlet H, Dahl JB. The value of 'multi-modal' or 'balanced' analgesia in postoperative pain treatment. Anesth Analg. 1993;77:1048-1056.
22. Moiniche S, Hjortso NC, Hansen BL, Dahl JB, Rosenberg J, Gebuhr P, Kehlet H. The effect of balanced analgesia on early convalescence after major orthopaedic surgery. Acta Anaesthesiol Scand. 1994;38:328-335.
23. Etches RC. Respiratory depression associated with patient-controlled analgesia: a review of eight cases. Can J Anaesth. 1994;41(2):125-132.
24. Parker RK, Holtmann B, White PF. Patient-controlled analgesia. Does a concurrent infusion improve pain management after surgery? JAMA. 1991;266(14):1947-1952.
25. Parker RK, Holtmann B, White PF. Effects of a night-time opioid infusion with PCA therapy on patient comfort and analgesia requirements after abdominal hysterectomy. Anesthesiology. 1992;76:362-367.
26. James MFM, Heijke SAM, Gordon PC. Intravenous tramadol versus epidural morphine for post-thoracotomy pain relief. A placebo-controlled, double-blind trial. Anesth Analg. 1996;83:87-91.
27. Korpela R, Korvenoja P, Meretoja OA. Morphine-sparing effect of acetaminophen in pediatric day-case surgery. Anesthesiology. 1999;91:442-447.
28. Schug SA, Sidebotham DA, McGuinnety M, Thomas J, Fox L. Acetaminophen as an adjunct to morphine by patient-controlled analgesia in the management of acute postoperative pain. Anesth Analg. 1998;87:368-372.
29. Moore A, Collins S, Carroll D, McQuay H. Paracetamol with and without codeine in acute pain: a quantitative systematic review. Pain. 1997;70:193-201.
30. Wan Po A Li, Zhang WY. Systematic overview of co-proxamol to assess analgesic effects of addition of dextropropoxyphene to paracetamol. BMJ. 1997;315:1565-1571.
31. Birmingham PK, Tobin MJ, Henthorn TK, Fisher DM, Berkelhamer MC, Smith FA, Fanta KB, Cote CJ. Twenty-four-hour pharmacokinetics of rectal acetaminophen in children: an old drug with new recommendations. Anesthesiology. 1997;87:244-252.
32. Baer GA, Rorarius MGF, Kolehmainen S, Selin S. The effect of paracetamol or diclofenac administered before operation on post operative pain and behaviour after adenoidectomy in small children. Anaesthesia. 1992;47:1078-1080.
33. Montgomery JE, Sutherland CJ, Kestin IG, Sneyd JR. Morphine consumption in patients receiving rectal paracetamol and diclofenac alone and in combination. Br J Anaesth. 1996;77;445-447.
34. Power I, Noble DW, Douglas E, Spence AA. Comparison of IM ketorolac trometarol and morphine sulphate for pain relief after cholecystectomy. Br J Anaesth. 1990;65:448-455.
35. Picard P, Bazin JE, Conio N, Ruiz F, Schoeffler P. Ketorolac potentiates morphine in postoperative patient-controlled analgesia. Pain. 1997;73(3):401-406.
36. Hawkey CJ. Future treatments for arthritis: New NSAIDs, NO NSAIDs, or no NSAIDs? Gastroenterology. 1995;109:614-616.
37. Glass PSA, Estok P, Ginsberg B, Goldberg JS, Sladen RN. Use of patient-controlled analgesia to compare the efficacy of epidural to intravenous fentanyl administration. Anesth Analg.1992;74:345-351.
38. Hashemi K, Middleton MD. Subcutaneous bupivacaine for postoperative analgesia after herniorrhaphy. Ann R Coll Surg Engl. 1983;65(1):38-39.
39. Owen H, Galloway DJ, Mitchell KG. Analgesia by wound infiltration after surgical excision of breast lumps. Ann R Coll Surg Engl. 1985:67(2):114-115.
40. Tverskoy M, Cozacov C, Ayache M, Bradley EL, Kissin I. Postoperative pain after inguinal herniorrhaphy with different types of anesthesia. Anesth Analg. 1990;70:29-35.
41. Adams WJ, Avramovic J, Barraclough BH. Wound infiltration with 0.25% bupivacaine not effective for postoperative analgesia after cholecystectomy. Aust N Z Surg. 1991;61:626-630.
42. Egan TM, Herman SJ, Doucette EJ, Normand SL, McLeod RS. A randomized controlled trial to determine the efficacy of fascial infiltration of bupivacaine in preventing respiratory complications after elective abdominal surgery. Surgery. 1988;104:734-740.
43. Gibbs P, Purushotham A, Auld C, Cuschieri RJ. Continuous wound perfusion with bupivacaine for postoperative wound pain. Br J Surg. 1988;75:923-924.
44. Johansson B, Gilse H, Hallerback B, Dalman P, Kristoffersson A. Preoperative local infiltration with ropivacaine for postoperative pain relief after cholecystectomy. Anesth Analg. 1994;78:210-214.
45. Levack ID, Holmes JD, Robertson GS. Abdominal wound perfusion for the relief of postoperative pain. Br J Anaesth. 1986;58:615-619.
46. Dierking GW, Dahl JB, Kanstrup J, Dahl A, Kehlet H. Effect of pre- versus post-operative inguinal field block on postoperative pain after herniorraphy. Br J Anaesth. 1992;68:344-348.
47. Ejlersen E, Andersen HB, Eliasen K, Mogensen T. A comparison between preincisional and postincisional lidocaine infiltration and postoperative pain. Anesth Analg. 1992;74:495-498.
48. Orntoft S, Longreen A, Moiniche S, Dhal JB. A comparison of pre- and postoperative tonsillar infiltration with bupivacaine after tonsillectomy. A pre-emptive effect? Anaesthesia. 1994;94:151-154.
49. Turner GA, Chalkiadis G. Comparison of preoperative with postoperative lignocaine infiltration on postoperative analgesic requirements. Br J Anaesth. 1994;72:541-543.