Figure 1. The incidence of severe pain in the PACU (Postambulatory care unit) after surgery. Approximately 5.3% of patients complain of severe pain (pain score of 7 to 10 out of 10) in the PACU. In the ASU (Ambulatory Surgical Unit, just before the patient is discharged to home), 1.7% of patients complain od severe pain. Twenty-four hours later, 5.3% complain of severe pain. That is very important. About 90% of patients in severe pain in the PACU, after surgery, are likely to call the physician at 3:00 in the morning of inadequate pain management. Physicians have got to control the pain early on, following any surgical procedure, otherwise, the physician and the patient will face the consequences.
Another of the potential complications following surgery is the development of chronic pain. The incidence of post-surgical pain that persists well beyond what might be expected (i.e. greater than 3-6 months) can be alarmingly high. The exact incidence of persistent postoperative pain remains controversial, but has been reported after numerous surgical procedures including limb amputation, thoracotomy, mastectomy, cholecystectomy, and inguinal hernia surgery [1, 2].
Estimates of chronic pain for various procedures include [14]:
2.3% to 4% following arthroscopic knee surgery
2.1% to 5% following carpal tunnel surgery
13.6% following ankle surgery
0.8% to 13% following total knee arthroplasty
7% to 37% for wrist fractures
4.5% to 40% following fasciectomy for Dupuytren’s contracture
Clearly there is significant variability in the incidence of chronic pain for each of these procedures, and specific risk factors for its development have been identified. These include, among others, preoperative pain of greater than one month’s duration, intensity of acute postoperative pain, psychological vulnerability and anxiety, and a surgical approach with risk of nerve damage [1].
Despite the identification of chronic post-surgical pain syndromes, little is known about the underlying mechanisms, natural history, and response to therapy of each syndrome [3]. It is now recognized that acute pain (nociceptor function) is dynamic and may be altered following tissue injury, which may contribute to persistent pain [4, 5].
Operative procedures produce an initial delivery of incoming pain signals (afferent barrage of pain) and generate a secondary inflammatory response, both of which contribute substantially to postoperative pain. The signals have the capacity to initiate prolonged changes in both the peripheral and central nervous system that will lead to the amplification and prolongation of postoperative pain. Increased peripheral sensitization to pain (a reduction in the threshold of nociceptor afferent peripheral terminals) is a result of inflammation at the site of surgical trauma [4] (Figures 2 and 3).
Figure 3. Surgical trauma leads to the release of inflammatory mediators at the site of injury, resulting in a reduction in the pain threshold t the site of injury (primary hyperalgesia) and in the surrounding uninjured tissue (secondary hyperalgesia). Peripheral sensitization results from a reduction in the threshold of nociceptor afferent terminals secondary to surgical trauma. Central sensitization is an activity-dependent increase in the excitability of spinal neurons (spinal wind-up) as a result of persistent exposure to afferent input from peripheral neurons. CNS = central nervous system, BK = bradykinin, PGs = prostaglandins, and 5-HT = serotonin.
It is important to administer these analgesics prior to the development of severe pain. Effective preventative analgesic techniques may not only be useful in reducing acute pain but also chronic post-surgical pain and disability.
This review will examine the efficacy of utilizing a variety of preemptive or preventative analgesic techniques aimed at reducing chronic pain following surgery. Five chronic postsurgical pain syndromes that are important clinically to physicians are complex regional pain syndrome, phantom limb pain, chronic donor site pain, postthoracotomy pain syndrome, and postmastectomy pain syndrome.
Complex Regional Pain Syndrome
Complex regional pain syndrome (CRPS) is a disorder characterized by the presence, following a noxious event, of regional pain and sensory changes such as temperature alterations, abnormal skin color, abnormal sudomotor activity, and/or edema [10]. Its onset is associated with a history of trauma (that is often innocuous) or immobilization.
The Consensus Conference of the International Association for the Study of Pain (IASP) has identified two forms of CRPS: CRPS type I (formerly known as reflex sympathetic dystrophy) and CRPS type II (formerly known as causalgia) [12]. Patients with CRPS I or CRPS II can have sympathetically maintained pain or sympathetically independent pain. Patients with CRPS may present with components only of sympathetically maintained pain or sympathetically independent pain, or more commonly a combination of pain from each [13].
The incidence of CRPS occurring after surgery is variable, and may be underreported [14]. Approximately 20% of CRPS patients who present to chronic pain clinics have a history of prior surgical procedures in the affected area [14-16]. Most reports of postoperative CRPS occur in the orthopedic population, especially after operations on the extremities. Estimates for various procedures include 2.3% to 4% following arthroscopic knee surgery, 2.1% to 5% following carpal tunnel surgery, 13.6% following ankle surgery, 0.8% to 13% following total knee arthroplasty, 7% to 37% for wrist fractures, and 4.5% to 40% following fasciectomy for Dupuytren’s contracture [14].
The use of regional nerve blocks that provide for a perioperative sympathectomy may be advantageous for those CRPS patients requiring surgery. It has been our practice to administer a stellate ganglion block to patients with CRPS undergoing upper extremity surgical procedures in the presence of local or general anesthesia. In a retrospective study of 100 CRPS patients undergoing surgery on the affected upper extremity, we observed a reduction in the recurrence of CRPS when performing a perioperative stellate ganglion block [17]. In this study, all signs and symptoms of CRPS had resolved before surgery. After completion of the surgical procedure, half of the patients (n=50) underwent a stellate ganglion block, while the other half (n=50) received no intervention. The recurrence rate of CRPS during the 12-month period following surgery was significantly lower in those patients receiving a perioperative stellate ganglion block (n=5; 10%) compared with those receiving no intervention (n=36; 72%, p<0.05).
In addition to stellate ganglion blocks, patients undergoing upper extremity surgical procedures may benefit from the perioperative sympathectomy provided by either brachial plexus block or intravenous regional anesthesia (IVRA) with clonidine. Clonidine possesses peripheral analgesic properties in patients with sympathetically maintained pain, possibly because it reduces the release of norepinephrine from prejunctional alpha-2-adrenoceptors in the periphery [18]. We have previously shown that IVRA with lidocaine and the alpha-2-adrenergic agonist, clonidine (1 µg/kg), is an effective technique for managing both acute postoperative pain [19] and symptoms of CRPS [20]. A prospective study of four anesthetic techniques (general anesthesia, IVRA with lidocaine, IVRA with lidocaine and clonidine, and axillary block) for 300 consecutive patients undergoing fasciectomy for Dupuytren’s contracture confirmed a beneficial effect of the latter two regional techniques [21]. Significantly (p<0.01) more patients developed postoperative CRPS in the general anesthesia group (n=25; 24%) and IVRA lidocaine group (n=12; 25%) compared to either the axillary block group (n=5; 5%) or the IVRA lidocaine and clonidine group (n=3; 6%).
In addition to perioperative regional blocks, the use of pharmacologic agents including calcitonin, mannitol, vitamin C, corticosteroids, carnitine, and ketanserin have been advocated for the prevention of postoperative CRPS [14]. Interestingly, only vitamin C has been shown to be beneficial in prospective, placebo-controlled studies [22, 23]. Vitamin C is a natural antioxidant that is reported to scavenge both hydroxyl radicals [24] and superoxide radicals that produce hydroxyl and other free radicals [25] that may be responsible for the pathogenesis of CRPS. Zollinger et al. [22] evaluated the efficacy of administering either 500 mg vitamin C or placebo daily for 50 days to 123 adults with 127 wrist fractures. There was a significant reduction in the incidence of CRPS in the vitamin C group (7%) compared to the placebo group (22%) at 1-year follow-up (95% CI for differences 2-26%). Cazeneuve et al. [23] confirmed the benefits of vitamin C in a prospective nonrandomized study of 195 patients with wrist fractures presenting for surgery. Patients receiving vitamin C (1 g daily) for 45 days, starting on the day of fracture had a five-fold lower incidence of CRPS (2.1% versus 10%, p<0.05). This simple, safe, and inexpensive technique may have significant implications in the development of protocols for the prevention and management of CRPS.
Finally, the role of preventative multimodal analgesic techniques in conjunction with physical therapy and rehabilitation following surgery appears to be a promising technique for reducing the incidence of post-surgical CRPS. A recent retrospective study of 1,200 patients undergoing anterior cruciate ligament (ACL) surgery examined the efficacy of administering a preventative multimodal analgesic technique (n=500) versus a standard postoperative pain protocol (n=700) [26, 27]. Patients in the preemptive multimodal group received acetaminophen 1,000 mg every 6 hours and rofecoxib 50 mg daily starting 48 hours prior to surgery. In addition, 30 minutes prior to surgery, a femoral nerve block and an intraarticular injection of bupivacaine/clonidine/morphine were performed. Postoperative analgesia included acetaminophen, rofecoxib, controlled-release oxycodone and a cryotherapy cuff.
In contrast, patients in the standard postoperative analgesic group received no preemptive analgesics prior to surgery and were administered ibuprofen and acetaminophen with oxycodone on an as needed basis postoperatively. All patients were subsequently enrolled in a 6 month accelerated rehabilitation protocol. This study revealed significantly lower pain scores (p<0.01) and greater number of patients able to complete this prescribed 6 month rehabilitation protocol (p<0.01) among those receiving multimodal treatment [26]. In addition, a significantly (p<0.001) higher incidence of complications was observed at 1-year follow up in the standard treatment group compared to the preemptive multimodal group [27]. Long-term complications included a higher incidence of anterior knee pain (14% versus 4%), greater number of patients requiring repeat arthroscopy for lysis of scar tissue (8% versus 2%), and a higher incidence of CRPS (4% versus 1%) in the standard analgesic group compared to the preemptive analgesic group, respectively (p<0.01).
Ketamine is undergoing a resurgence. For decades, anesthesiologists used ketamine for induction of general anesthesia at 2 mg/kg. However, some patients hallucinated and the use of the drug waned.
We are beginning to see a resurgence using small, low-dose ketamine. Low doses inhibit the NMDA receptors, which is responsible for central sensitization, and can work synergistically with many other analgesics. A recent lead article in Anesthesiology noted that low dose IV ketamine in combination with an epidural had a significant reduction (p<0.05) in not just acute pain, but it eliminated chronic postsurgical pain one year later.
(Figure 4) Hallucinations are extremely rare with low doses of subanesthestic ketamine of about 20 to 30 mg in the average adult. Furthermore, the risk of hallucinations declines with repeated use of ketamine.
Figure 4. Drawing depicting the sites of action of ketamine. The study by Lavand'homme et al. showed that low dose IV ketamine in combination with an epidural had a significant reduction in acute pain and reduced chronic postsurgical pain one year later. (Lavand’homme P, DeKock M, Waterloos H. Intraoperative epidural analgesia combined with ketamine provides effective preventative analgesia in patients undergoing major digestive surgery. Anesthesiology 2005;103:813-20)
Chronic, intractable CRPS is often associated with major depression. A recent randomized trial using a single low dose infusion of ketamine for 40 minutes showed a rapid and prolonged response in treating major depression. [96] The authors commented:
“To our knowledge, there has never been a report of any other drug or somatic treatment (ie, sleep deprivation, thyrotropin-releasing hormone, antidepressant, dexamethasone, or electroconvulsive therapy) that results in such a dramatic rapid and prolonged response with a single administration.”
Another recent study from Germany suggests that there may be a role for high dose ketamine in treating severe CRPS refractory to treatment. [97, 98] To date, 30 patients have been treated. Treatment is initiated by bolus injections of ketamine (0.5 mg/kg) and midazolam (2.5-5 mg) until deep sedation is reached. Patients are intubated and the therapy is maintained with infusions of ketamine (3-7 mg/kg/h) and midazolam (0.15-0.3 mg/kg/h) over five days. On the fifth day infusions are slowly tapered.
So far, nine of the 30 patients have experienced complete and permanent remission from their previously intransigent symptoms. Of the remaining 21 patients, all of whom had at least a partial remission, seven were entirely pain-free for six to seven months, after which the pain slowly returned. Ten of the patients are now being treated with subanesthetic doses of ketamine in an attempt to boost the initial effect. Side effects have been minimal.
The FDA-approved drug insert supports the safety ketamine:
"Ketamine has a wide margin of safety; several instances of unintentional administration of overdoses of ketamine (up to ten times that usually required) have been followed by prolonged but complete recovery.”
Click Here For CNN Report On Ketamine Coma
Click Here For 7-Minute Video Demonstration Of Ketamine Infusion
Conclusion
The development of chronic pain following surgery continues to be a major source of morbidity following a variety of surgical procedures. Despite its prevalence, our understanding of chronic postoperative pain and the potential means of risk reduction are somewhat deficient. We need to classify these chronic pain syndromes according to symptoms and mechanisms and greater emphasis needs to be placed on preventing its development. Preventative analgesic techniques may play a role in reducing the incidence of certain chronic post-surgical pain syndromes. It has been suggested that effective treatment of acute pain, particularly when accompanied by a neuropathic element, may prevent the development of chronic post-surgical pain syndromes [95]. The reduction in chronic pain may be attributed to a preventative analgesic effect in which a reduction in spinal cord neuroplasticity derives from prompt reduction in the perioperative noxious afferent input associated with surgery. Whether or not the timing of an analgesic intervention in the perioperative period ends up being a critical part of the puzzle, the value of aggressive and comprehensive pain control for surgical patients should not be underestimated. In order to effectively prevent the development of central neuroplasticity we need to administer analgesics during both the pre-, intra-, and postoperative periods.
Further, we have learned from postthoracotomy pain studies that regional blockade by itself may be insufficient in providing complete pain relief and preventing central sensitization. A multimodal analgesic regimen utilizing regional blockade, NSAIDs, and other peripheral and centrally-acting analgesics administered throughout perioperative period may be the most efficacious strategy. In other words, the provision of “intensive and prolonged, multimodal analgesic interventions” [7] may serve to insulate the susceptible neural pathways from a continuous barrage of nociceptive input over the long term, resulting in improved comfort to our patients and possibly a reduction in chronic pain. Future large-scale randomized controlled trials are necessary to support the use of preventative multimodal analgesic techniques in reducing chronic post-surgical pain syndromes.
Selected Articles by Dr. Reuben:
1. Scott S. Reuben, Evan F. Ekman. The effect of initiating a preventive multimodal analgesic regimen on long-term patient outcomes for outpatient anterior cruciate ligament reconstruction surgery. Anesth Analg 2007;105:228-32
Click HERE For PDF of Article
2. Scott S. Reuben, Rene Pristas, Duane Dixon, Shameema Faruqi, Lakshmi Madabhushi, and Steven Wenner. Fasciectomy for Dupuytren’s Contracture: A Prospective Observational Study of Four Anesthetic Techniques. Anesth Analg 2006;102:499–5
Click HERE For PDF of Article
3. Scott S. Reuben. Preventing the Development of Complex Regional Pain Syndrome after Surgery. ANESTHESIOLOGY 2004; 101:1063–5.
Click HERE For PDF of Article
4. Scott S. Reuben and Asokumar Buvanendran. Preventing the Development of Chronic Pain After Orthopaedic Surgery with Preventive Multimodal Analgesic Techniques. J Bone Joint Surg Am. 2007;89:1343-1358.
Click HERE For PDF of Article
Part II: Algorithm for Perioperative Management of CRPS Patients
Part III: Highlights for Patients
References
PREVENTING OTHER CHRONIC PAIN DISORDERS
Phantom limb pain (English)
Chronic donor site pain (English)
Postthoracotomy pain syndrome (English)
Postmastectomy pain syndrome (English)
