Regional Anesthesia: If, How, When?

Steven L. Shafer, M.D. Friday, November 22, 1996

There are many aspects of regional anesthesia worth reviewing. In preparing these lecture notes I noticed that there are already three talks on regional anesthesia given by Dr. Abouleish: Modern trends in Spinal Anesthesia, Epidural Anesthesia Safety and Practice, and Combined Spinal and Epidural Techniques. To avoid repetition with these lecture, while addressing the question: If, How, When I elected to focus on the question of preemptive analgesia. Specifically, should you select regional anesthesia, even if a general anesthetic is also planned, in order to reduce post-operative pain? If so, how should you provide the block to assure preemptive analgesia? Lastly, when should you place the block? Does time make a difference? 1. IF: Does preemptive analgesia exist? The first big question about preemptive analgesia is whether it exists at all. If you block the painful stimulus from ever reaching the central nervous system, will you provide a clinical benefit to your patient? The data are conflicting. The difficulty with assessing clinical trials on preemptive analgesia is well summarized in a recent review by McQuay.1 In this review, McQuay observes that although there is considerable support for preemptive analgesia from basic animal research, the evidence from randomized clinical trials is generally lacking. Specifically, the results from trials with local anesthetics, opioids, and NSAIDs all produce conflicting results, probably from lack of power and vague measures of outcome. First, lets consider several studies that suggest that preemptive analgesia does occur in patients. In a convincing demonstration of preemptive analgesia, Katz and colleagues prospectively studied 30 patients undergoing elective thoracotomy.2 The patients were randomized to receive epidural fentanyl (4 g/kg in 20 mls saline) either prior to incision or 15 minutes after incision. At 6 hours following surgery subjects in the group receiving epidural fentanyl prior to incision had pain scores of 2.6 vs 4.7 in those receiving epidural fentanyl following incision, a significant difference. PCA morphine use also differed significantly in the period from 12-24 hours, with subjects receiving epidural fentanyl prior to incision requiring 12 mg of morphine over the 12 hour period, while subjects receiving epidural fentanyl following incision required 26 mg of morphine over the same time period. It is hard to imagine a mechanism other then preemptive analgesia that would explain why a difference in timing of only 20-30 minutes or so in epidural fentanyl administration would cause such a big difference pain scores at 6 hours or in post-operative morphine use. Another study by Katz and colleagues again was strongly suggestive of preemptive analgesia. In this study, patients undergoing lower abdominal surgery were randomized to receive either 15 mls 0.5% epidural bupivacaine 35 min before incision or 15 mls 0.5% epidural bupivacaine 30 min after incision.3 The patients who received epidural analgesia prior to incision had reduced morphine use from 12-24 hours following surgery. Again, it is hard to imagine an explanation for the reduced morphine dose from 12-24 hours from just a 1 hour delay in epidural bupivacaine administration other than preemptive analgesia.

2 Others have extended the concept to include full balanced analgesic regimen that combines epidurally administered opioids and local anesthetics to block ascending nocioceptive influences, systemic NSAIDS to inhibit prostaglandin synthesis, and systemic metamizole to induce descending inhibition. Rockemann investigated the compared the results of balanced analgesia administered before and after surgery with placebo. The balanced analgesic technique consisted of 15-20 ml 1% mepivacaine, followed by an infusion of 0.1 ml/kg/hr during surgery, 5 mg epidural morphine, 75 mg intramuscular diclofenac, and 1000 mg of intravenous metamizole. This was either administered before abdominal surgery, before wound closure, or not at all. All patients received postoperative morphine via PCA. While post-operative pain scores were similar in the three groups, those receiving the balanced analgesic regimen prior to surgery had reduced morphine consumption compared with those receiving the regimen before wound closure (95 vs 111 mg) and those receiving a placebo regimen (137 mg).4 Similarly, Richardson observed considerable preemptive effect following thoracic surgery. Their treatment group received systemic opioids and NSAIDs preoperatively and a nerve block prior to thoracic incision. The control group received none of these interventions.5 Postoperatively the authors reported better pulmonary function and reduced analgesic requirements in the treatment group, suggesting preemptive analgesia with the balanced analgesic technique. Preemptive analgesia is not just confined to neuraxial regional techniques. Pasqualucci and colleagues demonstrated that 20 mls of 0.5% bupivacaine solution administered into the peritoneal cavity before laparoscopy cholecystectomy under general anesthesia resulted in decreased postoperative pain when compared with placebo and with 20 mls administered at the conclusion of surgery.6 Since the local anesthetic concentrations in tissues would be higher in the post-operative period when the 20 mls were administered at the end of the anesthetic, the observation that patients who received the local anesthetic at the beginning of surgery were more comfortable postoperatively suggests that the intraperitoneal bupivicaine caused preemptive analgesia. It is clear that administration of a local anesthetic will reduce analgesic requirements in the immediate post-operative period. For example, Badner and colleagues demonstrated that administration of 30 mls of 0.5% bupivacaine with 1:200,000 epinephrine into the knee joint following knee replacement resulted in reduced morphine requirements at the time of discharge (59 mg 81 mg) compared with placebo.7 It is hard to know if this is simply effective postoperative regional anesthesia, because there was no benefit to placing the local anesthetic at the beginning vs the end of the procedure. This highlights some of the difficulty with studies in preemptive analgesia. Here we learn that placing bupivacaine in the knee after knee replacement reduced morphine concentrations post-operatively, but this is the analgesic effective preemptive or is this simply a good method of providing postoperative analgesia? While the above may appear to provide convincing evidence of preemptive analgesia, it is important to note that the effects have generally been small. For example, the complex technique employed by Rockmann with epidurally administered opioids and mepivacaine, diclofenac, and metamizole resulted in an average reduction of post-operative morphine use from 137 mg to 95-111 mg (depending on whether the block was administered before surgery or before wound surgery.) This is a pretty small effect given the great effort extended to provide analgesia, and it is the effect compared with placebo. The difference between pre-incisional vs post-incisional administration of local anesthesia was just 95 vs 111 mg of morphine, a difference that was not significant. Given that the effects in most studies have been small

3 (although statistically significant), it is not surprising that some studies fail to show any evidence of preemptive analgesia. For example, in a study of thoracic extradural block, Aguilar and colleagues found that there was no difference in pain scores and PCEA opioid delivery between subjects who received local anesthesia prior to thoracotomy and subjects who received placebo.8 Pryle and colleagues randomized women requiring abdominal hysterectomy to 15 ml 0.5% bupivacaine via epidural catheter, administered either before incision or before waking.9 They observed no difference in morphine dose, pain scores, and verbal pain ratings over the first 24 hours. Abdulatif and colleagues found no evidence of reduction in postoperative morphine requirements following active vs placebo administration of interpleural bupivacaine in women undergoing cholecystectomy.10 Dierking and colleagues did not find any evidence of preemptive analgesia when comparing preoperative vs postoperative field-block for inguinal herniorrhaphy.11 In 32 patients who were randomized to either a block immediately before or immediately after general anesthesia and surgery, there was no significant difference in VAS scores, verbal pain assessments, time to ambulation, or morphine use. The difficulties of this type of study are highlighted in a study by Kavanagh and colleagues.12 The compared a balanced analgesic regimen consisting of preoperative administration of morphine 0.15 mg/kg i.m. with perphenazine 0.03 mg/kg-1 i.m. and a rectal suppository of indomethacin 100 mg. After induction of anesthesia, the treatment group received intercostal nerve block with 0.5% bupivacaine and adrenaline 1:200,000 (3 ml) in the interspace of the incision and in the two spaces above and two spaces below. The placebo group only received midazolam 0.05 mg/kg. In the first 6 hours following thoracic surgery the morphine consumption was significantly less in the treatment group, as would be expected from the use of nerve blocks and systemic analgesics. However the morphine consumption on postoperative days 1 and 2 were greater in the treatment group. Thus, the aggressive use of a balanced analgesic regimen appeared to offer no preemptive analgesic effect. The animal data supporting preemptive analgesia are complex. In rats Yashpal and colleagues examined whether lumbar intrathecal lidocaine given before or after formalin injection of the hind paw attenuated postinjury nocioception.13 The found that treatment 5 min before injection, but not treatment 5 min after injection, reduced late phase nocioception after injection of 2.5% formalin. Interestingly, only the response to 2.5% formalin was suppressed. The lidocaine was ineffective in suppressing the late phase nocioception if 3.75% or 5% formalin was injected in the paw. Additionally, rats receiving a deep injury caused by 100 l of formalin injected into the knee joint demonstrated reduced nocioception response if they received intravenous morphine and intrathecal bupivacaine prior to injury, but not if they received only the intrathecal bupivacaine without the systemic opioid, or if the bupivacaine was given after the injury. In randomized human volunteers Pedersen and colleagues demonstrated that preemptive block of the saphenous nerve reduced primary and secondary hyperalgesia following thermal injury to the leg.14 There was no effect on either erythema or blistering in the injured region from the saphenous block. Let us return to the first question: can regional anesthesia induce preemptive analgesia? The answer is almost surely yes, but the effect is fairly small. As suggested by the rat data and some of the negative human studies, as the painful stimulus becomes stronger, it requires more profound blockade to produce an effect. In the rat, the response to the profound pain induced by formalin injection into the knee joint required a combination of local anesthetics and opioids.

4 Should you perform regional anesthetics to provide for preemptive analgesia? The answer obviously depends on the risks involved, which have to be balanced against the potential benefits. If you are capable of providing effective postoperative analgesia by other means, then the potential benefits may be small. However, in patients in whom your ability to provide postoperative analgesia is questionable, or whom might tolerate postoperatively pain very poorly (e.g., patients with significant coronary artery disease), then the potential benefits of providing preemptive regional analgesia are increased. On a closely related topic (although a bit tangential to regional anesthesia per se) is the question of whether systemic drugs can cause preemptive analgesia. Animal investigations have suggested that systemic opioids probably do not prevent spinal sensitization. Abram and Olson recently demonstrated in a rat model that neither systemic alfentanil nor morphine, administered in doses that produce profound analgesia in standard analgesic tests, did not prevent hyperalgesia that followed subcutaneous formalin injection under general anesthesia.15 However, some clinical trials have suggested that morphine given intravenously prior to incision results in preemptive analgesia.16 For example, Richmond and colleagues compared the PCA morphine use for 24 hours following surgery in patients receiving 10 mg of morphine prior to incision or following peritoneal closure. They found that patients given the drug prior to incision had significantly reduced morphine requirements. However, what is not clear from their data is whether this is because the patients who received the morphine late in the operation had satisfactory analgesia on emergence from anesthesia. Given that morphine takes 45 minutes to an hour to produce peak effect, it may be that the patients in the late group required considerably more morphine early in recovery, thus artifactually raising their apparent morphine requirement over the first 24 hours. Similarly, using electrical stimulation to measure pain thresholds, Wilder-Smith and colleagues have demonstrated that fentanyl administration before surgery decreases spinal sensitization and augments supraspinal analgesia.17 As was the case for preemptive analgesia from regional techniques, there are negative studies as well as positive studies. Wilson and colleagues observed no preemptive analgesic effect from systemic administration of alfentanil given either before or after skin incision for total abdominal hysterectomy.18 Tverskoy and colleagues investigated whether analgesic regimens which included fentanyl or ketamine as part of the induction (and hence, preincisional) would be associated with less postoperative pain at 48 hours pain than techniques that did not involve systemic analgesics.19 They found at 48 hours patients in the fentanyl and ketamine groups were significantly more tolerant of pressure on the wound than in the group without systemic analgesics during surgery. However, spontaneously reported pain and pain on movement were identical for all three groups. Thus, there was a very small effect on one index, pain reported when the wound was pressed. However, by virtually all standard clinical indices there was no benefit. 2. HOW does one provide regional anesthesia to produce preemptive analgesia? The data on this seem very clear. To produce preemptive analgesia, it is necessary to produce a nearly complete blockade of the afferent noxious stimulation. This is illustrated by the rat studies Yashpal. It is also evident in the results reported by Shir and colleagues. These investigators compared 3 three different anesthetic regimens for radical prostatectomy: epidural anesthesia, a combined epidural/general technique, and general anesthesia.20 As would be expected, the patients receiving only epidural analgesia required larger doses of bupivacaine than those in which the epidural was supplemented with general anesthesia (129 vs 98 mg). What is

5 interesting is that on the second and third postoperative day patients receiving epidural anesthesia required significantly less PCEA (fentanyl + bupivacaine) than patients in the either the epidural/general group or in the general anesthesia group. There was no evidence for preemptive analgesia in the combined epidural/general anesthesia group when compared with the general anesthesia group. Thus, only those subjects in whom the afferent noxious stimulation were completely blocked demonstrated preemptive analgesia. Preemptive analgesia can be accomplished through neuraxial blocks, nerve blocks, or even just instillation of local anesthesia into the peritoneal cavity. The type of blockade is not important. However, the adequacy of the blockade is the common component of successfully providing preemptive analgesia. If neuraxial blockade is used, it appears that the combination of a local anesthetic and an opioid is probably the best combination for assuring an adequate blockade. 3. WHEN should the block be placed. The studies suggest that the block should be placed before any noxious stimulation, i.e., before incision. Thus, if an epidural catheter is placed preoperatively for postoperative pain management, it probably makes sense to dose both local anesthetics and opioids into the catheter before incision, rather than wait until the end of anesthesia. A delay of even a few minutes following incision appears to eliminate the preemptive analgesic effect. In summary, a benefit of regional anesthesia is the provision of preemptive analgesia. Technical aspects of neuraxial blockade will be discussed in three lectures by Dr. Abouleish. In this lecture we will consider whether preemptive analgesia is an important benefit of regional anesthesia. If it is, we will discuss the principles of regional anesthesia that help ensure a preemptive analgesic effect.
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McQuay HJ. Preemptive analgesia: a systematic review of clinical studies. Annals of Medicine, 1995 Apr, 27(2):249-56. 2 Katz J; Kavanagh BP; Sandler AN; Nierenberg H; Boylan JF; Friedlander M; Shaw BF. Preemptive analgesia. Clinical evidence of neuroplasticity contributing to postoperative pain [see comments]. Anesthesiology, 1992 Sep, 77(3):439-46. 3 Katz J; Clairoux M; Kavanagh BP; Roger S; Nierenberg H; Redahan C; Sandler AN. Preemptive lumbar epidural anaesthesia reduces postoperative pain and patient-controlled morphine consumption after lower abdominal surgery. Pain, 1994 Dec, 59(3):395-403. 4 Rockemann MG; Seeling W; Bischof C; Borstinghaus D; Steffen P; Georgieff M. Prophylactic use of epidural mepivacaine/morphine, systemic diclofenac, and metamizole reduces postoperative morphine consumption after major abdominal surgery. Anesthesiology, 1996 May, 84(5):1027-34. 5 Richardson J; Sabanathan S; Mearns AJ; Evans CS; Bembridge J; Fairbrass M. Efficacy of preemptive analgesia and continuous extrapleural intercostal nerve block on post-thoracotomy pain and pulmonary mechanics. Journal of Cardiovascular Surgery, 1994 Jun, 35(3):219-28. 6 Pasqualucci A; de Angelis V; Contardo R; Colo F; Terrosu G; Donini A; Pasetto A; Bresadola F. Preemptive analgesia: intraperitoneal local anesthetic in laparoscopic cholecystectomy. A randomized, double-blind, placebocontrolled study. Anesthesiology, 1996 Jul, 85(1):11-20. 7 Badner NH; Bourne RB; Rorabeck CH; MacDonald SJ; Doyle JA. Intra-articular injection of bupivacaine in kneereplacement operations. Results of use for analgesia and for preemptive blockade. Journal of Bone and Joint Surgery. American Volume, 1996 May, 78(5):734-8. 8 Aguilar JL; Rincon R; Domingo V; Espachs P; Preciado MJ; Vidal F. Absence of an early pre-emptive effect after thoracic extradural bupivacaine in thoracic surgery. British Journal of Anaesthesia, 1996 Jan, 76(1):72-6.

Pryle BJ; Vanner RG; Enriquez N; Reynolds F. Can pre-emptive lumbar epidural blockade reduce postoperative pain following lower abdominal surgery? Anaesthesia, 1993 Feb, 48(2):120-3. 10 Abdulatif M; al-Ghamdi A; Gyamfi YA; el-Sanabary M; al-Metwally R. Can preemptive interpleural block reduce perioperative anesthetic and analgesic requirements? Regional Anesthesia, 1995 Jul-Aug, 20(4):296-302. 11 Dierking GW; Dahl JB; Kanstrup J; Dahl A; Kehlet H. Effect of pre- vs postoperative inguinal field block on postoperative pain after herniorrhaphy. British Journal of Anaesthesia, 1992 Apr, 68(4):344-8. 12 Kavanagh BP; Katz J; Sandler AN; Nierenberg H; Roger S; Boylan JF; Laws AK. Multimodal analgesia before thoracic surgery does not reduce postoperative pain [see comments]. British Journal of Anaesthesia, 1994 Aug, 73(2):184-9. 13 Yashpal K; Katz J; Coderre TJ. Effects of preemptive or postinjury intrathecal local anesthesia on persistent nociceptive responses in rats. Confounding influences of peripheral inflammation and the general anesthetic regimen. Anesthesiology, 1996 May, 84(5):1119-28. 14 Pedersen JL; Crawford ME; Dahl JB; Brennum J; Kehlet H. Effect of preemptive nerve block on inflammation and hyperalgesia after human thermal injury. Anesthesiology, 1996 May, 84(5):1020-6. 15 Abram SE; Olson EE. Systemic opioids do not suppress spinal sensitization after subcutaneous formalin in rats. Anesthesiology, 1994 May, 80(5):1114-9. 16 Richmond CE; Bromley LM; Woolf CJ. Preoperative morphine pre-empts postoperative pain [see comments]. Lancet, 1993 Jul 10, 342(8863):73-5. 17 Wilder-Smith OH; Tassonyi E; Senly C; Otten P; Arendt-Nielsen L. Surgical pain is followed not only by spinal sensitization but also by supraspinal antinociception. British Journal of Anaesthesia, 1996 Jun, 76(6):816-21. 18 Wilson RJ; Leith S; Jackson IJ; Hunter D. Pre-emptive analgesia from intravenous administration of opioids. No effect with alfentanil. Anaesthesia, 1994 Jul, 49(7):591-3. 19 Tverskoy M; Oz Y; Isakson A; Finger J; Bradley EL Jr; Kissin I. Preemptive effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia [see comments]. Anesthesia and Analgesia, 1994 Feb, 78(2):205-9. 20 Shir Y; Raja SN; Frank SM. The effect of epidural versus general anesthesia on postoperative pain and analgesic requirements in patients undergoing radical prostatectomy. Anesthesiology, 1994 Jan, 80(1):49-56.