Key Concepts in Analgesic Therapy

Chapter 12


Key Concepts in Analgesic Therapy



THIS chapter presents the key concepts of opioid analgesic administration. Included is a discussion of the recommended approach to managing all types of pain: multimodal analgesia. The research related to preemptive analgesia, accelerated multimodal postoperative rehabilitation, and prevention of persistent postsurgical pain is reviewed. The pros and cons of the various methods for opioid analgesic dosing are described, and an introduction to the concept of patient-controlled analgesia (PCA) and alternative uses of analgesic devices is provided.



Multimodal Analgesia


As discussed in Section III, a multimodal regimen combines drugs with different underlying mechanisms, such as nonopioids, opioids, local anesthetics, and anticonvulsants. This approach allows lower doses of each of the drugs in the treatment plan, which lowers the potential for each to produce adverse effects (Ashburn, Caplan, Carr, et al., 2004; Kim, Kim, Nam, et al., 2008; Marret, Kurdi, Zufferey, et al., 2005; Schug, 2006; Schug, Manopas, 2007; White, 2005). Further, multimodal analgesia can result in comparable or greater pain relief than can be achieved with any single analgesic (Busch, Shore, Bhandari, et al., 2006; Cassinelli, Dean, Garcia, et al., 2008; Huang, Wang, Wang, et al., 2008).


Multimodal analgesia is discussed most often in the context of acute pain treatment; however, pain has multiple underlying mechanisms and is a multifaceted phenomenon, underscoring the importance of using a multimodal approach to manage all types of pain; this should be the rule, rather than the exception (Argoff, Albrecht, Irving, et al., 2009; Kehlet, Wilmore, 2008; Kehlet, Jensen, Woolf, 2006) (see Section I). A sound treatment plan relies on the selection of appropriate analgesics from the opioid, nonopioid, and adjuvant analgesic groups.



WHO Analgesic Ladder for Cancer Pain Relief


Probably the most well-known example of combining analgesics from the nonopioid, opioid, and adjuvant analgesic groups is the World Health Organization (WHO) analgesic ladder (Figure 12-1), which was proposed in the early 1980s as a guide to the management of persistent cancer pain (WHO, 1986; Meldrum, 2005). Still today, it is the clinical model for pain therapy (Ripamonti, Bandieri, 2009). The analgesic ladder focuses on selecting analgesics on the basis of the intensity of the pain using analgesics from each of the analgesic groups and, to some extent, building on previously effective analgesics.




Steps 1, 2, and 3


The three steps of the WHO analgesic ladder address different intensities of pain. However, patients do not always have mild pain at the bottom of the ladder and do not necessarily progress through each of the three levels of pain intensity. Some patients with cancer pain will have moderate to severe pain initially, whereas others may progress directly from mild pain to severe pain. Therefore, treatment of cancer pain does not necessarily begin with step 1, progress to step 2, and follow with step 3 (Eisenberg, Marinangeli, Birkhahn, et al., 2005). If the patient initially has severe pain, step 3 treatment considerations are appropriate (Marinangeli, Ciccozzi, Leonardis, et al., 2004).


Step 1 of the analgesic ladder addresses mild pain by suggesting a nonopioid analgesic, such as acetaminophen or an NSAID, and the possibility of an adjuvant analgesic, particularly if the patient has neuropathic pain. It should be noted, however, that the term adjuvant, when used in this ladder, refers to both the adjuvant analgesics and the adjuvant drugs that are added to analgesics to reduce adverse effects (e.g., laxatives for opioid-induced constipation; see Chapter 19).


If pain is mild to moderate and not relieved by a nonopioid (with or without an adjuvant), step 2 recommends adding an opioid. In other words, the next level of analgesia builds on the previous analgesics. If a nonopioid relieves some but not enough pain, it is continued and an opioid is added. This action, of course, must be predicated on an assessment that indicates the favorable risk:benefit ratio for the continued treatment with the nonopioid drug. Although, in the past, the decision to stop the nonopioid and start an opioid rather than add an opioid to the nonopioid often was considered merely a common mistake, new information about the gastrointestinal (GI) and the cardiovascular (CV) risk of NSAID therapy alters this view. Rather, the decision to use or continue an NSAID cannot be mostly determined by the pain intensity, or the analgesic ladder guideline, but rather, must be decided based on an evaluation of cumulative risk over the remaining time (see Chapter 6).


The clinical usefulness of step 2 is frequently debated (Ripamonti, Bandieri, 2009). An early meta-analysis demonstrated no differences between the safety and efficacy of NSAIDs (step 1 analgesics) and so-called “weak” opioids (step 2 analgesics) (Eisenberg, Berkey, Carr, et al., 1994). Pharmacologically, no difference exists between most of the drugs used on step 2 and those used on step 3. Because the same three groups of analgesics are considered at both steps, the ladder could be reduced to only 2 steps.


In clinical practice, the reason for having step 2 is to assist the clinician in selecting an opioid that may be conventionally preferred for the treatment of moderate to severe pain in the patient who is opioid-naïve, or nearly so. For example, mild to moderate pain is often treated with oral analgesics in a fixed combination of opioid and nonopioid, usually acetaminophen or sometimes aspirin (see Chapter 5). Although the problem with fixed combinations is that the dose of acetaminophen (or other nonopioid) limits the escalation of the opioid dose, the benefit is that it helps the clinician to select a formulation that is generally safe for the patient with very limited opioid exposure (and also allows a potentially more convenient way of combining the nonopioid and opioid). Common examples of opioid/nonopioid fixed combinations are as follows:



To avoid exceeding the recommended maximum daily dose of 4 g of acetaminophen, the patient cannot take more than 8 tablets per day of those containing 500 mg of acetaminophen or 12 tablets per day of those containing 325 mg of acetaminophen. Recent discussions by the United States Food and Drug Administration (U.S. FDA) encourage clinicians to consider the maximum daily dose of acetaminophen to be 2.6 g, or 8 tablets per day of those formulations containing 325 mg of acetaminophen (U.S. FDA, 2009b; Harris, 2008). This provides more of a safety margin if the patient unintentionally takes other acetaminophen-containing (usually over-the-counter) drugs.


Oxycodone is commonly used in these fixed combinations and is also considered a step 3 drug, a useful opioid for escalating pain. Therefore if a fixed combination of acetaminophen and oxycodone is used at step 2, plain (single-entity) oxycodone may be continued at step 3. Plain acetaminophen can also be continued at appropriate doses.


To avoid step 2 and the need to change opioids or formulations as pain increases, mild to moderate pain may be treated with low doses of plain oxycodone, morphine, or hydromorphone. These mu agonists may be continued throughout the course of therapy because doses of these may be escalated for the relief of increasingly severe pain. Studies have demonstrated the effectiveness of this approach. In 110 opioid-naïve patients with moderate to severe cancer pain, oral morphine at a starting dose of 15 mg/day (10 mg in older adults) followed by titration was found to be well tolerated and effective (Mercadante, Porzio, Ferrera, et al., 2006). A randomized controlled study showed that first-line use of so-called “strong” opioids (e.g., morphine, fentanyl, or methadone) in terminally ill cancer patients resulted in significantly better pain relief and patient satisfaction and necessitated fewer changes in the pain treatment plan than when patients followed the 3-step WHO ladder approach (Marinangeli, Ciccozzi, Leonardis, et al., 2004). Similarly, another study of patients with moderate cancer pain compared the 3-step WHO ladder approach with a modified version that moved patients directly from step 1 to step 3 as pain increased (Maltoni, Scarpi, Modonesi, et al., 2005). Direct progression from step 1 to step 3 resulted in a lower percentage of days with worst pain but were associated with a higher incidence of anorexia and constipation despite laxative treatment. The researchers promoted this approach but underscored the importance of attention to careful management of adverse effects.


Opioid analgesics recommended at step 3 should be available orally and by a variety of other routes of administration so that the opioid need not be changed if the route of administration must change. For example, if a patient taking oral morphine has a temporary episode of nausea and vomiting, morphine may be continued by administering it by other routes, such as rectally or subcutaneously. Many opioids, such as morphine, hydromorphone, and fentanyl, are available by a variety of routes of administration (see Chapter 14).


In much of the world, opioids used at step 3 are either available in a modified-release formulation, or they are long half-life drugs. After dose titration (which in the case of the modified-release drugs often can be accomplished using short-acting formulations), these drugs can be administered with relatively long dosing intervals, which may be more convenient and support adherence to the therapy. For example, morphine and oxycodone have fairly short half-lives—2 to 4 hours (Gutstein, Akil, 2006)—and are available in modified-release formulations that allow dosing every 12 hours.


The existence of active metabolites should be considered when selecting an opioid for long-term therapy. Morphine has active metabolites: morphine-6-glucuronide [M6G] and morphine-3-glucuronide [M3G]. These metabolites accumulate in patients with renal dysfunction and may be associated with toxicity (Johnson, 2007). Hydromorphone (Dilaudid) is a common alternative to morphine, and a modified-release formulation is available in some countries and most recently in the United States. Hydromorphone’s metabolite (hydromorphone-3-glucouronide) can also accumulate in patients with renal dysfunction (Johnson, 2007), but the clinical consequences appear to be limited (Kurella, Bennett, Chertow, 2003). Nonetheless, it has been noted that opioid toxicity can recur when morphine is replaced with hydromorphone in patients with renal dysfunction, and dose should be reduced in such patients (Launay-Vacher, Karie, Fau, et al., 2005). Cautious use of fentanyl in patients with renal dysfunction has been suggested as an alternative when metabolite accumulation is a concern (Dean, 2004; Launay-Vacher, Karie, Fau, et al., 2005) (see Chapter 13 for more on morphine, hydromorphone, and fentanyl).


Other important recommendations that accompany the WHO analgesic ladder are to administer analgesics orally whenever possible and to administer them “by the clock” or around the clock (ATC) to prevent the return of pain.



Patient Example: WHO Ladder


A 59-year-old man has arm, shoulder, and chest pain as a result of invasion of the chest wall and brachial plexus by an apical lung cancer. He has not responded to radiation therapy and chemotherapy. History is remarkable for a major gastrointestinal hemorrhage from a gastric ulcer 2 years earlier. Analgesic use is limited to an occasional acetaminophen for headaches. He is married and has two adult children.





Patient encounter 3


Pain severity and descriptors: Aching, burning, constant, radiating from chest and shoulder into arm, moderate to severe (7 to 8/10). Disturbed sleep and ability to concentrate.


Inferred pain pathophysiology: Neuropathic and somatic.


Analgesic selection: Percocet was changed to morphine sulfate, 15 mg, + acetaminophen, 650 mg PO, every 4 hours, ATC, with morphine sulfate, 15 mg, breakthrough doses (BTDs) every 1 to 2 hours as needed (PRN). An adjuvant, desipramine 25 mg was added at night.


Step on analgesic ladder: 3.


Rationale: Step 3 of the analgesic ladder was selected because the patient’s pain was severe. An adjuvant drug was added because of the neuropathic component of the pain. The opioid dose was determined as follows: 10 mg of morphine PO is considered to be equianalgesic to 7 to 10 mg of oxycodone PO (= 2 Percocet). Because the pain was not controlled, the equianalgesic dose was increased by 50%. The BTD of morphine sulfate of 15 mg PO every 1 to 2 hours PRN was selected on the basis of a 5% to 15% ratio of his 24-hour baseline morphine dose. The dose, 15 mg, is in fact 17% of the 24-hour dose but was chosen because of the available tablet size.


Possible adverse effects: Constipation, sedation, nausea, dry mouth.


Outcome: Thirty-six hours later, the patient called to say that his pain control had markedly improved but only in the setting of frequent BTDs. Overall, with BTDs, pain was 75% better. He had required nine BTDs in the previous 24 hours (15 mg × 9 = an additional 135 mg of morphine). Consequently, his baseline morphine dose was increased by approximately the equivalent amount, to 30 mg PO every 4 hours. The dose chosen was a slightly lower dose than the total of the baseline plus BTDs but reflected the available tablet size and was considered likely to provide adequate analgesia. Rescue medication continued to be available. His BTD was adjusted to reflect 5% to 15% of the new 24-hour baseline dose of 180 mg, at 30 mg every 2 hours PRN. Again, this dose, 30 mg, is in fact 17% of the 24-hour dose but was chosen because of the available tablet size. Adjustment was undertaken because the 15 mg dose was not providing effective analgesia.


Good pain control was reached with BTDs used only once or twice a day in relation to a specific activity. Once stable pain relief was established, he was switched to a modified-release oral morphine preparation, allowing for 12-hour dosing. The equivalent dose he received was 90 mg q12h; the BTD dose was left unchanged. The desipramine was increased every 3 to 4 days until the analgesia it provided seemed maximal and he was sleeping well; the dose reached was 100 mg q hs. Mild nausea and mental clouding resolved after a few days. Constipation was treated with a bowel regimen (refer to Chapter 19).


He did relatively well for several months; however, his disease was progressing, and intermittent upward titration of his baseline dose was undertaken on the basis of his BTD requirement. Four months later he was taking modified-release morphine, 180 mg every 12 hours, and the BTD remained at 30 mg short-acting morphine every 1 to 2 hours PRN (within 5% to 15% of baseline and providing effective analgesia).



Patient encounter 4


A fall at home resulted in a fractured femur. The patient elected to have surgery as a means of allowing prompt mobilization that could facilitate an improved quality of life. Preoperatively his leg pain was severe, and analgesic therapy needed to be adjusted.


Pain severity and descriptors: Sharp, 9 to 10/10 on movement.


Inferred pain pathophysiology: Somatic. Acute pain superimposed on persistent chest wall and arm pain.


Analgesic selection: Morphine was continued, but the route of administration was changed from an oral to an IV infusion. His infusion rate was started at 7.5 mg/h with 4 mg BTDs available every 30 minutes PRN.


Step on analgesic ladder: 3.


Rationale: Because of the severity of the pain, the equianalgesic dose was increased by 50% when switching from the oral to the IV route. Using a 3:1 oral/IV ratio, his infusion rate was started at 7.5 mg/h (360 mg + 180 mg = 540 mg oral morphine/24 h = 180 mg IV morphine/24 h = 7.5 mg/h), with 4 mg BTDs available every 30 minutes PRN. (The total hourly BTD was approximately 5% of the total daily dose, and the first dose given provided effective analgesia. If it had not, the rescue dose would have been escalated by 30% to 50%.) Although several BTDs were required in the first few hours, the need for these subsided. Surgical recovery was uneventful. Five days after surgery, he was able to take PO medications and was using very occasional BTDs. He was, however, anxious about the planned switch to oral pain medication and requested that it be done gradually. The IV infusion was initially decreased to approximately half (3.5 mg/h), and he was given the equivalent oral dose, 130 mg every 12 hours, in a modified-release oral morphine preparation. He continued to have IV BTDs available to him as before. Forty-eight hours later, his IV infusion had been discontinued, and he was taking the equivalent modified-release morphine dose of 260 mg every 12 hours by mouth. BTDs of oral short-acting morphine sulfate, 60 mg (5% to 15% of 24-hour opioid dose) were available to him every 1 to 2 hours PRN. Desipramine was restarted at 25 mg q hs and gradually titrated up to its previous level of 100 mg.


Outcome: The patient’s pain remained well controlled at home on oral analgesics until his death 4 weeks after discharge. Ongoing assessment and reassessment by the nurse in liaison with the patient’s primary physician were critical components in managing the analgesic approach to this man’s pain. The assessment included the effectiveness of relief, the duration of relief, the effectiveness of BTDs, and the presence and management of adverse effects.


Adapted from Coyle, N., & Portenoy, R. K. (1996). Pharmacologic management of cancer pain. In R. McCorkle, M. Grant, M. Frank-Stromborg M, et al. (Eds.), Cancer nursing: A comprehensive textbook, Philadelphia, Saunders.



Effectiveness of the WHO Analgesic Ladder


The use of the WHO ladder in combination with appropriate dosing guidelines is capable of providing adequate pain relief in 70% to 90% of individuals with persistent cancer pain (Hanks, Cherny, Fallon, 2004). This was demonstrated in a 10-year study of 2118 patients, which further indicated that clinically significant pain reduction usually occurred within the first week of treatment (Zech, Grond, Lynch, et al., 1995). Good to satisfactory pain relief was maintained in 88% of the patients over the entire treatment period, and only 12% required invasive procedures for pain relief, such as nerve blocks. Of note is the fact that both opioids and nonopioids were prescribed in 73% of the patients. Also, oral opioid doses reported in this study suggest that the clinicians understood that no ceiling exists on the analgesia of mu agonists because some patients received up to 2400 mg/day of oral morphine. A more recent retrospective study of 3238 patients with advanced cancer reported good pain relief (VAS scores less than 30) in 89% of those following the principles of the WHO analgesic ladder (Bhatnagar, Mishra, Srikanti, et al., 2008). The WHO ladder approach has also been adapted to effectively treat phantom limb pain (Mishra, Bhatnagar, Gupta, et al., 2008) and pain in patients with end-stage renal disease (Salisbury, Game, Al-Shakarchi, et al., 2009).



Preemptive Analgesia for Postoperative Pain Management


In the early 1980s, studies of the spinal cord changes occurring in the context of peripheral afferent input—changes that were termed central sensitization (Woolf, 1983)—generated interest in the therapeutic potential of interventions that could be implemented before tissue injury occurred, in the hope of blocking or reducing this phenomenon (Dahl, Moiniche, 2004; Grape, Tramer, 2007) (see Section I for more on central sensitization). A multimodal approach that includes local anesthetics to block sensory input and NSAIDs and opioids, which act in the periphery and in the CNS, initiated preoperatively and continued intraoperatively and throughout the postoperative course, was suggested as ideal preemptive analgesic treatment (Woolf, Chong, 1993). Since then, numerous studies have investigated a wide variety of agents and techniques in an attempt to show a preemptive analgesic effect (Dahl, Moiniche, 2004; Moiniche, Kehlet, Dahl, 2002). Unfortunately, these studies showed that this approach alone did not result in major benefits postoperatively.


Testing the hypothesis of preemptive analgesia requires comparing the effectiveness of an intervention applied before the surgical incision (experimental group) with the effectiveness of the same or very similar intervention applied only after the surgical incision (control group). The notion that such a simple approach could reduce or possibly prevent postoperative pain stimulated an abundance of research on preemptive analgesia; however, many of the studies had flawed research designs and led to flawed conclusions (Bromley, 2006; Grape, Tramer, 2007; Moiniche, Kehlet, Dahl, 2002; Dahl, Moiniche, 2004). For example, some studies compared preoperative analgesic administration with placebo or no treatment and claimed a preemptive effect when treatment was associated with a subsequent reduction in pain. These and other inaccurate claims of positive results led to an overly optimistic perception of the effectiveness of preemptive analgesia (Grape, Tramer, 2007).


An extensive review of the literature on preemptive analgesia concluded that preoperative (preemptive) administration of systemic opioids did not improve postoperative analgesia (Moiniche, Kehlet, Dahl, 2002). None of the studies reviewed demonstrated a reduction in pain intensity scores in the groups of patients who received preemptive (preincision) analgesia; analysis of the weighted mean differences in pain scores favored the groups who received postoperative (postincision) analgesia. An updated review in 2004 reported the same results (Dahl, Moiniche, 2004).


The general consensus is that preemptive administration of analgesics does not offer major clinical benefits (i.e., consistent immediate postoperative pain relief or reduced need for supplemental analgesia) (Bromley, 2006; Dahl, Moiniche, 2004; Grape, Tramer, 2007; Kelly, Ahmad, Brull, 2001; Moiniche, Kehlet, Dahl, 2002). However, the disappointing research related to preemptive analgesia does not mean that postoperative benefits cannot be realized with aggressive perioperative analgesic interventions. It has been suggested that research and clinical practice should redirect the focus from “preemptive” (timing of a single [most often] conventional intervention) to “protective” analgesia whereby aggressive, sustained multimodal interventions are initiated preoperatively and continued throughout the intraoperative and postoperative periods (Moiniche, Kehlet, Dahl, 2002; Dahl, Moiniche, 2004). Consistent with this approach are the goals of immediate postoperative pain reduction and prevention of prolonged and pathologic pain (Kelly, Ahmad, Brull, 2001). The key underlying pain management principles are to intervene before the onset of pain, use a multimodal approach, and administer analgesics in the proper dose and manner, on time, and for an adequate duration of time (Kelly, Ahmad, Brull, 2001).



Accelerated Multimodal Postoperative Rehabilitation


Advances in the field of pain management have led to more aggressive use of analgesics, but it is unclear if this has resulted in significant improvements in patient outcomes such as the quality of postoperative recovery and long-term function (Liu, Wu, 2007a). An unacceptable number of surgical patients continue to experience delays in recovery, complications, and the need for extended hospital stays (Kehlet, Wilmore, 2008). An extensive review of research (18 meta-analyses, 10 systematic reviews, 8 randomized controlled trials, and 2 observational database articles) revealed that there are insufficient data to show that high-quality postoperative pain management, such as regional analgesia and IV PCA, impacts the incidence and severity of postoperative complications (Liu, Wu, 2007b). The researchers suggested that improvements will depend on the integration of pain control into a comprehensive postoperative rehabilitation program that includes fluid balance and early mobilization and nutrition. For example, a variety of positive outcomes, such as early return of GI function and shortened length of hospital stay, have been observed in patients undergoing major surgery when epidural analgesia is combined in a multimodal postoperative rehabilitation plan (Basse, Billesbolle, Kehlet, 2002; Basse, Hjort Jakobsen, Billesbolle et al., 2000; Brodner, Van Aken, Hertle, et al., 2001; Kehlet, Wilmore, 2004). The use of multimodal strategies that attack the specific physiologic insults of surgery should be considered when developing postoperative treatment plans, particularly for patients who undergo major surgical procedures. For example, the IV administration of hypocaloric dextrose (glucose) 10% in addition to continuous epidural analgesia has been shown to inhibit the catabolic effects of surgery as demonstrated by postoperative suppression of whole-body protein breakdown (Lattermann, Wykes, Eberhart, et al., 2007; Schricker, Meterissian, Wykes et al., 2004).


Patient outcomes have historically been reported as morbidity and mortality data; however, a focus on patient-reported assessments as a subset of morbidity and mortality events may provide unique insight into specific areas that need more intense research and clinical focus (Liu, Wu, 2007a, 2007b). An exhaustive review of the literature evaluated the effect of postoperative analgesia on patient-assessed indicators, which included a variety of aspects of analgesia, presence of adverse effects, health-related quality of life, quality of recovery, and patient satisfaction (Liu, Wu, 2007b). The researchers identified a lack of high-quality data and called for the development of validated tools to measure patient-reported outcomes and well-designed research that examines these as the primary study end points.


Establishing the link between good pain management and improvements in patient outcomes will require changes in the way health care is administered (Kehlet, Wilmore, 2008; Liu, Wu, 2007a, 2007b). Traditional practices in perioperative care, such as prolonged bed rest, withholding oral nutrition for extensive periods, and routine use of tubes and drains, are being increasingly challenged and replaced with evidence-based decision making (Pasero, Belden, 2006). This and other factors have led to the evolution of fast track surgery and enhanced postoperative recovery (Kehlet, Wilmore, 2008). In a review of the literature, Kehlet and Wilmore (2008) describe the evidence that supports key principles of implementing what is referred to as accelerated multimodal postoperative rehabilitation. These are outlined in Box 12-1. Continuous multimodal pain relief is integral to this concept.



Guidelines



Box 12-1


Key Components to Accelerated Multimodal Postoperative Recovery




1. Preoperative patient education outlining the plan of care and emphasizing expectations of an active patient role in recovery


2. Perioperative optimization (e.g., preoperatively ensure optimal nutritional and hydration status; maximize pulmonary function; control underlying persistent pain; and reduce alcohol, tobacco, and medications that can cause intraoperative adverse events)


3. Surgical stress reduction (attenuation of neurohormonal response to the surgical procedure)



4. Pain reduction: Multimodal perioperative analgesic approaches that reduce postoperative pain and other discomforts, control the stress response, and allow early and aggressive recovery activities



5. Prevent and control nausea and other discomforts and adverse effects that interfere with recovery (e.g., implement multimodal strategies to prevent and treat nausea)


6. Aggressive postoperative rehabilitation measures (e.g., goal-directed ambulation, early discharge planning)


7. Evidence-based decision making with regard to care practices (e.g., challenge traditional practices that increase infection and pain, impede ambulation, and produce other adverse effects that impede recovery)



From Pasero, C., & McCaffery, M. Pain assessment and pharmacologic management, p. 308, St. Louis, Mosby. Data from Gan, T. J., et al. (2006). PONV management. http://www.medscape.com/viewprogram/4990. Accessed December 8, 2009; Jensen, K., Kehlet, H., & Lund, C. M. (2007). Post-operative recovery profile after laparoscopic cholecystectomy: A prospective, observational study of a multimodal anaesthetic regime. Acta Anaesthesiol Scand, 51(4), 464-471; Kehlet, H., & Wilmore, D. W. (2002). Multimodal strategies to improve surgical outcome. Am J Surg, 183(6), 630-641; Kehlet, H., & Wilmore, D. W. (2008). Evidence-based surgical care and the evolution of fast-track surgery. Ann Surg, 248(2), 189-198; Pasero, C. (2007). Procedure-specific pain management: PROSPECT. J PeriAnesth Nurs, 22(5), 335-340; Pasero, C., & Belden, J. (2006). Evidence-based perioperative care: Accelerated postoperative recovery programs. J PeriAnesth Nurs, 21(3), 168-177; PROSPECT: Procedure Specific Postoperative Pain Management. http://www. postoppain.org. Accessed December 8, 2009. Pasero C, McCaffery M. May be duplicated for use in clinical practice.



Tools that can be used to increase evidence-based perioperative pain management practice patterns are emerging. For example, a novel web-based program called PROSPECT (Procedure Specific Postoperative Pain Management) (http://www.postoppain.org), established by an international team of surgeons and anesthesiologists, posts evidence-based recommendations and algorithms to guide the health care team in decision making with regard to pain management according to specific surgical procedures (Pasero, 2007).



Persistent Postsurgical Pain


As many as 50% of patients undergoing surgical procedures, such as inguinal hernia repair; breast, cardiac, or thoracic surgery; leg amputation; and coronary artery bypass, experience persistent pain; in 2% to 10% of these individuals, the intensity of persistent postsurgical pain is severe (Kehlet, Jensen, Woolf, 2006). A study of 90 women who underwent abdominal hysterectomy pain for noncancer conditions found that 16.7% experienced persistent postoperative pain (Brandsborg, Dueholm, Nikolajsen, et al., 2009). The incidence of persistent post-mastectomy pain is reported to be as high as 65% (Smith, Bourne, Squair, et al., 1999).


Pain following traumatic injury is common as well. A multicenter study conducted in 69 hospitals in 14 states in the United States found that 62.7% of patients (N = 3047) reported injury-related pain at 12 months after a traumatic injury (Rivara, MacKenzie, Jurkovich, et al., 2008). A quarter of patients in an earlier study (N = 397) described pain that interfered with daily activity 7 years following limb-threatening lower extremity trauma; 40% reported high pain intensities (Castillo, MacKenzie, Wegener, et al., 2006).


Further research is needed, but multiple factors are thought to contribute to the likelihood of postsurgical pain, including surgical nerve injury, preexisting pain, and genetic susceptibility. For example, severe pre-amputation pain has long been associated with a higher incidence of phantom limb pain (Bach, Noreng, Tjellden, 1988; Katz, 1997; Nikolajsen, Ilkjaer, Kroner, et al., 1997). A 2-year study of 57 patients who underwent lower extremity amputation revealed that high levels of both pre- amputation pain and acute pain after amputation predicted persistent post-amputation pain (Hanley, Jensen, Smith, et al., 2007). Greater analgesic requirements during the immediate postoperative period following coronary artery bypass surgery predicted persistent pain (multiple anatomic sites) in a study of 736 patients (Taillefer, Carrier, Belisle, et al., 2006). Older patients tend to have a lower risk of developing persistent postsurgical pain than younger patients (Poobalan, Bruce, Smith, et al., 2003; Smith, Bourne, Squair, et al., 1999). For example, one study showed that patients under the age of 40 years old were at increased risk for persistent post-inguinal hernia repair pain (Poobalan, Bruce, King, et al., 2001). Another found that the prevalence of persistent chest and leg pain following cardiac surgery was 55% in patients who were less than 60 years of age and 34% in those over 70 years old (Bruce, Drury, Poobalan, et al., 2003). The reader is referred to an excellent review by Perkins and Kehlet (2000) that includes predictive factors, etiology, and progression of postsurgical pain conditions.


The presence of pain at 3 months after injury was a predictive factor for both the presence and the high severity of persistent pain following major trauma (Rivara, MacKenzie, Jurkovich, et al., 2008). Although the presence of persistent pain varied with age, it was more common in women and in those who had untreated depression before the traumatic injury in this study. Another study found that multiple factors influenced the likelihood of persistent pain 7 years after major lower extremity trauma (Castillo, MacKenzie, Wegener, et al., 2006). These included having less than a high school education, having less than a college education, low self-efficacy for return to usual major activities, a high level of alcohol consumption in the month prior to injury, and high pain intensity, high levels of sleep and rest dysfunction, and elevated levels of depression and anxiety at three months after hospital discharge. Interestingly, those who were treated with opioid analgesics during the first three months after discharge in this study had lower levels of persistent pain at 7 years, underscoring the importance of early initiation of aggressive pain management approaches.


The clinical presentation of persistent postsurgical or post-trauma pain is primarily the patient’s report of the features characteristic of neuropathic pain, such as continuous burning pain and pain beyond the expected time of pain resolution (see Section II for assessment of neuropathic pain). Strategies for preventing these persistent pain states are being investigated, but sustained multimodal pharmacologic approaches that target the underlying mechanisms of neuropathic pain described earlier in this section are recommended (Kehlet, Jensen, Woolf, 2006). See Section I for the underlying mechanisms of the pathology of pain and more on persistent postsurgical pain, and Sections III, IV, and V for discussion of the role of the various analgesics and techniques in the prevention of persistent postsurgical and posttrauma pain.

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