Preclinical Models of Postoperative Pain

Understanding of postoperative pain pathways in humans has been greatly enhanced by studies of incisional pain in animal models (Brennan 2011). The rat plantar foot incision model produces both thermal and mechanical (von Frey filaments) hypersensitivity to applied stimuli for about a 10-day period (Brennan et al 1996). Moreover, the model exhibits both primary hyperalgesia (stimuli in the immediate vicinity of the incision) and secondary hyperalgesia (stimuli at some distance from the wound) (Zahn and Brennan 1999). Decreased spontaneous activity is another means of assessing pain in animal surgical models because patients with postoperative pain are less willing to move around. This has been demonstrated in rats after laparotomy (Martin et al 2004), thoracic muscle incision (Kroin et al 2006), and knee surgery (Buvanendran et al 2008).

Clinical Research Studies of Surgical Pain

Experimental incision-induced primary hyperalgesia has been demonstrated in humans (Kawamata et al 2002). After a forearm incision, mechanical hypersensitivity 3 mm from the incision site lasted for 2 days. There was also a short-lived secondary hyperalgesia.

Patients receiving flank incisions for nephrectomy had a large area of mechanical hypersensitivity to von Frey filament stimulation that lasted at least 7 days after surgery, thus indicating persistent secondary hyperalgesia (Stubhaug et al 1997). Similarly, after an abdominal incision for colonic resection, patients had a large area of mechanical hypersensitivity for at least 3 days after surgery (Lavand’homme et al 2005).

Opioids

Dual-Acting Agents (Tapentadol, Tramadol)

Recently, a drug with a dual mode of action, tapentadol, was approved for moderate to severe pain but has not yet gained widespread use in clinical practice (Afilalo et al 2010). It exerts its analgesic action via the μ-opioid receptor and norepinephrine reuptake inhibition. Combining both effects in a single molecule eliminates the potential for the drug–drug interactions inherent in multiple-drug therapy. The analgesic effects of tapentadol are independent of metabolic activation, and it has minimal metabolites. The dual mode of analgesia is synergistic, as demonstrated by preclinical work. An immediate-release formulation of tapentadol was approved by the Food and Drug Administration (FDA) and has been used in the United States since 2008, with 50, 75, and 100 mg and the long-acting drug being approved in 2011. The drug is schedule II, and therefore all precautions that must be followed for other drugs in this category need to be strictly adhered to. The equipotent analgesic dose of 100 mg of tapentadol to oxycodone is 15 mg, and it needs to be administered every 4–6 hours.

This compound also has activity at the descending spinal pathway and hence may prove to be a very useful analgesic as more clinical experience is obtained in the postoperative setting. With equipotent doses of the narcotics, the incidence of PONV is lower with tapentadol than with oxycodone (Etropolski et al 2011). The concept of obtaining equipotent analgesia with decreased PONV can be of great benefit in treating postoperative pain and can lead to earlier discharge with significant cost savings (Kwong et al 2010). However, further clinical trials need to be carried out to demonstrate this benefit.

Tramadol may be appropriate for mild to moderate postoperative pain or in conjunction with a cyclooxygenase-2 (Cox-2) inhibitor for pain after anterior cruciate ligament (ACL) surgery (Bourne 2004). It is a centrally acting analgesic that binds to μ-opioid receptors and inhibits the reuptake of norepinephrine and serotonin. Tramadol is effective as a low-dose opioid for postoperative pain and has very low risk for respiratory depression. The combination of tramadol and acetaminophen can provide analgesia for moderate to severe postoperative pain. Tramadol has low risk for abuse and is not a scheduled drug.

Non-opioid Anti-hyperalgesics

In this section we discuss the use of adjuvant drugs (Buvanendran and Kroin 2007) during the postoperative period following major surgery. They are used as adjuvants to opioids or local anesthetics and are an integral part of the multimodal analgesia protocols (Buvanendran and Kroin 2009) to be discussed later.

Multimodal Analgesia

The theory behind multimodal anesthesia is that agents with different mechanisms of analgesia may have synergistic effects—or at least additive effects—in preventing or treating acute pain when used in combination. Thus, multimodal analgesia captures the effectiveness of individual agents at optimal dosages that maximize efficacy while attempting to minimize side effects from any one analgesic. These regimens must be tailored to individual patients while keeping in mind the procedure being performed, side effects of the individual medications, and patients’ pre-existing medical conditions (Buvanendran and Kroin 2009). The concept and theory of multimodal analgesia are not new; however, several novel pharmacological agents have emerged and can be added to the drug regimen to be used in this fashion. It is vital to realize that blocking the neuronal pathway with local anesthetics during surgery does not decrease the humoral biochemical responses that occur during surgery; the latter have to be inhibited by administering systemic pharmacological therapy (Buvanendran et al 2006). This is especially important in ambulatory or fast-track surgery protocols to hasten postoperative recovery and decrease hospitalization time (Kehlet and Wilmore 2008, Buvanendran and Thillainathan 2010).

Epidural or Intrathecal Local Anesthetics

Epidural analgesia and spinal/epidural analgesia have been used increasingly in recent years to control pain during and after labor (Loubert et al 2011; also see Chapter 55). When continuous epidural regimens are applied in a well-functioning acute pain service setting (Viscusi 2008), side effects are few and the benefits outweigh the risks. A meta-analysis of epidural PCA of opioids showed that it produced superior pain control in comparison to IV PCA for all types of surgeries (Wu et al 2005). Epidural analgesia also provided better pain relief than systemic opioids did for abdominal aortic surgery, and the overall incidence of cardiovascular complications, myocardial infarction, acute respiratory failure, gastrointestinal complications, and renal insufficiency was significantly reduced (Nishimori et al 2006).

Role of Peripheral Nerve Blocks

The increased safety of PNBs that has been made possible in the past 5 years through the use of ultrasound and the decreased quantity of the analgesic solution administered have made this method attractive to practitioners. PNB of the major nerves supplying the lower extremities has emerged as a good alternative (Fowler et al 2008) to the epidural technique for providing postoperative analgesia after surgery on the lower limb, especially with the current anticoagulation guidelines (Horlocker et al 2003). PNB can be achieved by single-shot blockade or by continuous infusion. For lower limb surgery, a femoral nerve block, a sciatic nerve block, an obturator nerve block, or a “3-in-1” block can be performed. Femoral nerve blocks are most commonly used for knee arthroplasty, either alone or in combination with a sciatic nerve block. After completion of the femoral nerve block, the patient is turned laterally for placement of a sciatic perineural catheter via a gluteal approach. Although anatomically an obturator nerve block in combination with a femoral block would provide greater analgesic benefit than a femoral plus sciatic block would, it is technically challenging to achieve an effective obturator block. A “3-in-1” block is intended to block the lateral femoral cutaneous, the femoral, and the obturator nerves.

Several studies have compared the analgesic efficacy and the incidence of side effects with PNBs (femoral alone or femoral plus sciatic) versus epidural analgesia. A systematic review of studies that compared the two techniques concluded that although the analgesic efficacy of both the epidural and PNB techniques was comparable, the incidence of side effects such as hypotension, urinary retention, and nerve injury was much lower with PNBs (Fowler et al 2008). In addition, nerve injuries associated with PNBs present much less adversity than a neuraxial injury. The review also evaluated the potential benefit of adding sciatic blocks to femoral blocks and concluded that there was no additional benefit. Although a lumbar plexus block has greater consistency with regard to blocking the obturator nerve than does an infra-inguinal femoral block (“3-in-1”), it is unclear whether there is any benefit in adding the obturator block. The incidence of quadriceps weakness with PNBs is higher and it can therefore interfere with early mobilization of patients, but there appears to be no difference in rehabilitative outcomes between the two groups at the time of discharge. Data are sparse on whether a continuous femoral nerve block is more effective than a single-shot femoral block. In a randomized trial the continuous mode lowered pain scores and increased opioid consumption significantly more than did the single-shot technique, but the length of stay and functional outcomes did not differ between the two groups (Salinas et al 2006). Although the exact mechanism is not clearly known, the addition of clonidine to a PNB at a dose of 100 μg appears to lead to prolongation of analgesia. Randomized controlled trials have shown that PNBs, especially continuous techniques, provide superior postoperative analgesia and improved outcomes in patients undergoing ACL surgery. For ACL surgery the femoral nerve can be blocked with bupivacaine (0.25–0.5%) or ropivacaine (0.2–0.5%), which can provide analgesia for surgery and the postoperative period.

Patients in whom a perineural femoral nerve catheter is placed typically receive an infusion of 0.1% ropivacaine via a patient-controlled regional anesthesia technique at a basal rate of 5 mL/hr plus a 3–5-mL bolus with a lock-out period of 60 minutes for discharge. The femoral perineural infusion is maintained for up to 24–48 hours postoperatively via disposable ambulatory pumps. Patients deemed appropriate for continuous nerve block analgesia at home need appropriate education before being discharged. The choice of analgesia for the postoperative period depends highly on the surgeon’s choice (Masursky et al 2008) of the timing of physical therapy. The presence of a femoral catheter, especially if the concentration of local anesthetic used is not dilute, can result in significant quadriceps weakness. In fact, there are case reports of patients falling (Williams et al 2007) and further injuring their knee when severe quadriceps weakness is present. Randomized trials comparing femoral nerve catheters with local anesthetics versus intra-articular (IA) injection of bupivacaine and morphine have demonstrated that both postoperative analgesics are equally effective and are associated with low pain scores and reduced narcotic consumption (Woods et al 2006). Preliminary studies suggest that continuous infusion of local anesthetics for peripheral nerve blockade may be very efficient and safe, even on an outpatient basis (Axley and Horn 2010).

A meta-analysis found that continuous peripheral nerve blockade decreased postoperative pain and opioid-related side effects when compared with opioids (Richman et al 2006). Addition of clonidine to local anesthetics, which in animal experiments extends the duration of a nerve block via inhibition of the hyperpolarization-activated cation current (Kroin et al 2004), prolongs the duration of analgesia and motor block in patients by about 2 hours but is associated with risk for orthostatic hypotension and fainting (Pöpping et al 2009).

Wound Instillation of Analgesics

Data obtained from patients undergoing knee replacement surgery support the intraoperative use of a local infiltration technique but not the postoperative use of wound catheter administration; however, there is little evidence to support use of the technique for hip replacement either intraoperatively or with a postoperative wound infusion catheter (Kehlet and Andersen 2011). In laparoscopic gastric procedures, intraperitoneal local anesthetic reduces the intensity of abdominal pain and postoperative opioid consumption (Kahokehr et al 2011). A newly developed liposomal formulation of long-acting bupivacaine is being considered for approval by the FDA. A single injection of the liposomal bupivacaine should last 72 hours and is currently being considered for infiltration of the local surgical site. Regional analgesia with this product has yet to be established.

Intra-articular Injections

IA analgesia has gained popularity for ambulatory surgery because of ease of administration, efficacy in achieving pain relief, and lack of systemic side effects (Rawal 2007). Procedures in which this has been demonstrated include knee and shoulder arthroscopy. However, the results are not conclusive; although several studies demonstrate a positive effect of IA analgesia, many others demonstrate the contrary. In addition, the very recent reports of chondrolysis following IA injection and infusion have led to further debate about its use (Fredrickson et al 2010). A variety of substances, including local anesthetics, opioids, NSAIDs, corticosteroids, α₂-adrenergic agonists, and NMDA receptor antagonists, have been used for IA analgesia from as early as 1985 (Hughes 1985). There are many variables in IA analgesia, including varying pharmacokinetic profiles and dosages of individual agents, and this has led to varying efficacy in pain relief and the use of creative combinations of drugs. One such combination that has been investigated is a bupivacaine–morphine combination, which demonstrated positive effects on postoperative pain in multiple studies (Khoury et al 1992, Guler et al 2004, Senthilkumaran et al 2010). After a systematic review it was concluded that IA morphine, 5 mg, was an optimal dose and could provide as much as 27 hours of analgesia postoperatively (Kalso et al 2002). When the dose range effect of IA morphine was examined, it was noted that the analgesic effect was “mild” (Gupta et al 2001).

IA ketorolac has been shown to have analgesic properties when compared with low doses of bupivacaine or morphine (Calmet et al 2004). Some authors have included ketorolac in combination with other drugs in IA injection; when used with bupivacaine and morphine, ketorolac, 60 mg by the IA route, led to a longer duration of analgesia following arthroscopic knee surgery and more patients well enough to return to work on postoperative days 1 and 2 (Ng et al 2006). Addition of a corticosteroid, methylprednisolone, 40 mg, to a morphine–bupivacaine injection also had a similar ability to enhance analgesia and allow patients to return to work earlier (Rasmussen et al 1998). Side effects of steroids, such as delayed wound healing or infection, were not observed with steroid injections (Wang et al 1998). Finally, the use of IA ketamine, 0.5 mg/kg, for outpatient arthroscopic surgery had analgesic effects when compared with placebo, although IA bupivacaine had a greater analgesic effect (Dal et al 2004).

Timing of the IA injection may be important. A single IA injection of morphine followed by another 10 minutes of tourniquet time improved postoperative analgesia (Whitford et al 1997). However, other studies have found no difference with varying tourniquet times (Klinken 1995) or after the tourniquet was deflated completely (Guler et al 2004). The type of procedure has also been linked to varying effects of IA agents. Patients undergoing knee procedures associated with a “high inflammatory response” (e.g., ACL reconstruction, lateral release, patellar shaving, and plica removal) had improved analgesia with morphine in comparison to bupivacaine. In contrast, patients undergoing diagnostic arthroscopy or partial meniscectomy (associated with “low inflammation”) had better pain control with bupivacaine than with morphine (Marchal et al 2003). Use of regional, neuraxial, or systemic analgesia in addition to IA analgesia has been noted as a possible confounding factor in evaluating the efficacy of IA studies. IA analgesia in shoulder surgery has been compared with parenteral analgesics and interscalene brachial plexus blockade (ISB). In patients undergoing arthroscopic acromioplasty, ISB was superior to IA analgesia or suprascapular nerve blockade. When compared with controls, only patients receiving ISB had significant reductions in pain scores and morphine consumption in the postanesthetic care unit (Singelyn et al 2004).

To provide longer-lasting analgesia, continuous IA infusions may be necessary. Following rotator cuff repair, implantation of an IA catheter with infusion of ropivacaine led to improvement in pain control for 12 hours postoperatively but no change in postoperative opioid consumption (Coghlan et al 2009). The authors argued that the use of continuous IA infusions was “not worth the substantial additional costs.” Similar findings were noted after arthroscopic subacromial decompression with a catheter in the subacromial space: improved pain scores but no change in opioid consumption (Harvey et al 2004). Other studies have shown a decrease neither in pain score nor in opioid consumption (Boss et al 2004). These findings have led Fredrickson and colleagues (2010) to question the utility of IA analgesia. Earlier studies were conducted on less painful shoulder procedures (arthroscopic, non–rotator cuff), which may explain the discrepancy with recent findings. Chondrolysis is the disappearance of articular cartilage as a result of dissolution of cartilage matrix and chondrocytes in a short period. This leads to severe osteoarthritis and long-term disability and is considered to be a rare disease of the shoulder (Bailie and Ellenbecker 2009). Animal models have recently indicated the chondrotoxicity of bupivacaine in rabbits (Gomoll et al 2006).

Various substances have been investigated for efficacy in relieving postoperative pain after arthroscopic surgery. The results have been mostly inconclusive. IA injection of opioids and local anesthetics may be safe in the knee. In theory, combinations of agents with different mechanisms of action may allow lower doses of individual drugs while potentiating the analgesic effect. Continuous and patient-controlled IA infusions are also discouraged because prolonged exposure to pharmacologic agents may be the trigger for the development of chondrolysis. Larger-scale studies are necessary to evaluate the benefit of substances other than opioids and local anesthetics. Additionally, determining the timing and optimum dosages and establishing safety profiles are crucial if IA analgesics are to evolve as a component of multimodal analgesic regimens.

Transdermal Fentanyl

The use of patient-controlled delivery has led to the development of other modalities that allow patient control in the delivery of opioid medications. Transdermal delivery systems permit demand dosing of fentanyl at a predetermined interval. The fentanyl HCl iontophoretic transdermal system (ITS) is a patient-controlled approach to analgesic delivery that may avoid some of the problems associated with IV PCA. Fentanyl ITS is a compact, needleless, self-contained system that is preprogrammed to deliver fentanyl, 40 μg, across the skin by means of an imperceptible low-intensity electrical current, a method known as iontophoresis. This system is under further research before being released for human use. Inhaled fentanyl has been tested in pediatric and adult patients. There are investigations of encapsulated liposomal inhaled fentanyl for acute pain—the advantage of this being that it can provide rapid onset and sustained release.

Topical Analgesics

Topical diclofenac exists in several forms, including diclofenac epolamine 1% topical patch, diclofenac sodium 1% topical gel, and diclofenac sodium 1.5% weight-in-weight (w/w) liquid. A recent review showed that topical NSAIDs are not only safe but efficacious as well in the treatment of acute soft tissue injuries and localized regions of pain, acute or chronic (Massey et al 2010). They did find a difference between placebo and topical NSAIDs with regard to local skin irritation, but the systemic side effects were less with the topical form. In fact, most current research points to the fact that topical application of diclofenac could lead to decreased systemic absorption and therefore fewer gastrointestinal and renal adverse events associated with this class of drug.

A review of the diclofenac epolamine topical patch discussed the benefits of the patch as opposed to NSAID gels or creams (McCarberg and Argoff 2010). Such benefits included application of a defined dose of diclofenac, drug delivery over an extended period (typically 12 hours), and ease of application. Application of diclofenac sodium 1% gel versus a placebo vehicle (composition identical to the gel component of the study drug) four times daily for 3 months was investigated for the treatment of osteoarthritis pain (Barthel et al 2009). The results of the study indicated superior analgesia from 1–12 weeks and improved function for the same duration. Diclofenac gel was tolerated as well as placebo. With regard to diclofenac 1.5% w/w liquid, it has been shown to be as efficacious as oral diclofenac in treating arthritis pain (Moen 2009). Gastrointestinal side effects were significantly less common, with local skin reactions being more common. A prospective study established the safety of topical diclofenac 1.5% w/w in a study in which 793 subjects were monitored for an average of 204 days and 144 subjects for 1 year (Shainhouse et al 2010). Application of the study drug, 40 drops four times daily, resulted in local skin reactions (dry skin, contact dermatitis, or dermatitis with vesicles) in 45.1% of the study participants. Twenty-four volunteers indicated a similar overall experience when using diclofenac gel and diclofenac liquid. However, they found the gel to have a less desirable scent and its consistency to be greasier and stickier than the diclofenac liquid (Galer 2010). When side effects have limited oral NSAID use in multimodal analgesia, it may be that intranasal (IN), IV, and topical formulations of NSAIDs could prove to be of benefit in the perioperative period and should be considered as tools that are emerging for multimodal analgesia.

Capsaicin, the active component of chili peppers, is a non-narcotic that acts at the transient receptor potential vanilloid 1 (TRPV1) receptor. It selectively stimulates unmyelinated C-fiber afferent neurons and causes the release of substance P. Following initial depolarization, continued exposure leads to desensitization and terminal die-back of C fibers that lasts several months An ultra-purified capsaicin (ALGRX 4975, 98% pure) has been investigated in a randomized, double-blind, placebo-controlled study of the analgesic efficacy of a single intraoperative wound instillation of 1000 μg of capsaicin after open-mesh groin hernia repair (Aasvang et al 2008). VAS pain scores assessed as area under the curve were significantly lower during the first 3 days postoperatively, but this effect was not observed after 72 hours. Local application of capsaicin during hernia repair does not lead to loss of sensory function in patients (Aasvang et al 2010). Further clinical trials have been carried out in patients undergoing total knee and hip arthroplasty, but the entire data have not been published to date. When capsaicin is used in the perioperative setting, the clinician must administer it well before the end of anesthesia to allow resolution of the acute burning sensation that occurs immediately after its application. The prolonged duration of analgesia produced by capsaicin could be extremely valuable in facilitating earlier rehabilitation after painful orthopedic surgery procedures. In contrast to local anesthetic, capsaicin does not affect motor or autonomic function and therefore will not interfere with postoperative rehabilitation. The capsaicin patch (NGX-4010), though used for various neuropathic chronic pain conditions, may be useful for acute pain in a multimodal fashion. This needs further large-scale randomized controlled trials.

Intranasal Analgesia

IN analgesia has evolved as a new route of administration of analgesics. The NSAID ketorolac given by this route reduced postoperative pain and opioid consumption following major surgery (Moodie et al 2008). When compared with placebo, patients receiving IN ketorolac had improved pain scores for third-molar extraction with bony impaction surgery (Grant and Mehlisch 2010). A randomized controlled trial in patients after abdominal surgery showed 26% less morphine consumed in the first 48 hours postoperatively in the ketorolac group (Singla et al 2010). Both studies remarked on the rapid onset of analgesia, which lasted up to 8 hours, and suggested that IN analgesia can be beneficial in ambulatory or fast-track surgery. The rapid onset and improved analgesia seen with IN ketorolac may be due to its higher penetration via the cribriform plate and into CSF, because it is known that higher CSF levels of NSAIDs are associated with greater analgesia.

Is There a Role for Pre-emptive Analgesia?

In a review of 66 studies (Ong et al 2005), it was concluded that the only pre-emptive treatment that improved all patient outcomes (pain intensity scores, supplemental analgesic consumption, and time to first analgesic consumption) was epidural anesthesia.

A newer concept suggests that the term “pre-emptive analgesia” should be abandoned and replaced with the term “preventive analgesia,” which means that to suppress central sensitization, analgesia should be maintained throughout the perioperative period; recent studies of preventive analgesia for persistent postoperative pain are promising (Pogatzki-Zahn and Zahn 2006).

Neuroendocrine

Surgical stress and pain elicit a consistent and well-defined metabolic response involving the release of neuroendocrine hormones and cytokines that lead to a myriad of detrimental effects (Blackburn 2011). In addition to the rise in catabolically active hormones such as catecholamines, cortisol, angiotensin II, and antidiuretic hormone, stress causes an increase in adrenocorticotropic hormone, growth hormone, and glucagon (Hagen et al 1980). Epinephrine, cortisol, and glucagon produce hyperglycemia by promoting insulin resistance and gluconeogenesis. They induce protein catabolism and lipolysis to provide substrates for gluconeogenesis. Aldosterone, cortisol, and antidiuretic hormone influence water and electrolyte reabsorption by promoting Na⁺ and water retention while expending potassium. This contributes to increases in the extravascular fluid compartment both peripherally and within pulmonary parenchymal tissue. Local release of cytokines such as interleukin-2 (IL-2), IL-6, and tumor necrosis factor may contribute to abnormal physiologic responses such as alterations in heart rate, temperature, blood pressure, and ventilation (Michie and Wilmore 1990). In fact, some clinical studies now demonstrate a direct correlation between IL-6 and the extent of surgical trauma and the stress response (Buvanendran et al 2006).

Cardiovascular

The cardiovascular effects of pain are initiated by the release of catecholamines from sympathetic nerve endings and the adrenal medulla, aldosterone and cortisol from the adrenal cortex, and antidiuretic hormone from the hypothalamus and by activation of the renin–angiotensin system. These hormones have direct effects on the myocardium and vasculature, and they augment salt and water retention, which places a greater burden on the cardiovascular system.

The sympathoadrenal release of catecholamines and the effects of angiotensin II may result in hypertension, tachycardia, and dysrhythmias and may lead to myocardial ischemia in susceptible patients as a consequence of the increased oxygen demand. In addition, a significant proportion of perioperative myocardial ischemia is related to reductions in myocardial oxygen supply without hemodynamic aberrations. Activation of the sympathetic nervous system may trigger coronary vasoconstriction, which may result in myocardial ischemia in patients with atherosclerotic coronary artery disease. This may occur through direct activation of cardiac sympathetic nerves, as well as through circulating catecholamines, which may contribute to hypercoagulability, a known mediator of adverse outcomes in patients with ischemic heart disease (Burke et al 2011).

Respiratory

For surgical procedures performed on the thorax and abdomen, pain-induced reflex increases in skeletal muscle tension may lead to decreased total lung compliance, splinting, and hypoventilation. These changes promote atelectasis, contribute to further ventilation–perfusion abnormalities, and result in hypoxemia. In major surgical procedures or in high-risk patients, these respiratory effects of pain may lead to a significant reduction in functional residual capacity ranging from 25–50% of preoperative values (Rawal et al 1984, Tzani et al 2011). Hypoxemia stimulates increases in minute ventilation. Although tachypnea and hypocapnia are common initially, prolonged increases in the work of breathing may result in hypercapnic respiratory failure. Pulmonary consolidation and pneumonitis may occur because of hypoventilation and further aggravate the clinical scenario. These sequelae are especially significant in patients with pre-existing pulmonary disease, upper abdominal and thoracic incisions, advanced age, or obesity.

Gastrointestinal

Pain-induced sympathetic hyperactivity may cause reflex inhibition of gastrointestinal function (Augestad and Delaney 2010). This promotes postoperative ileus, which contributes to postoperative nausea, vomiting, and discomfort and delays resumption of an enteral diet. Failure to resume early enteral feeding may be associated with postoperative morbidity, including septic complications and abnormal wound healing (Moore et al 1992, Dudrick and Palesty 2011).

Immunological

The pain-related stress response suppresses both cellular and humoral immune function (Kurosawa and Kato 2008) and results in lymphopenia, leukocytosis, and depression of the reticuloendothelial system. Many known mediators of the stress response are potent immunosuppressants, and both cortisol and epinephrine infusions decrease neutrophil chemotaxis (Davis et al 1991). These effects can lower resistance to pathogens and may be key factors in the development of perioperative infectious complications (Hopf and Holm 2008). When surgical manipulation of neoplasms causes release of tumor cells, the postoperative stress response may reduce the cytotoxicity of killer T cells. Increases in catecholamines, glucocorticoids, and prostaglandins in response to stress may impair the immunologic responses important for patients with neoplasms (Snyder and Greenberg 2010).

Besides reducing the neuroendocrine stress response, regional anesthesia can decrease myocardial work and oxygen consumption by reducing the heart rate, arterial pressure, and left ventricular contractility. With continuous epidural analgesia with local anesthetics, postoperative pulmonary function is improved (Pöpping et al 2008) and paralytic ileus reduced (Kehlet 2008).

Presurgical Factors

Preoperative pain intensity is a risk factor for persistent post-surgical pain (Katz and Seltzer 2009). For example, the incidence of chronic pain after total knee arthroplasty is increased in osteoarthritis patients who have more pain before surgery (Brander et al 2003). Recent studies have used experimental pain stimuli (e.g., heat) to quantify each subject’s pain sensitivity (Naert et al 2008, Granot 2009). Although the evidence is conflicting regarding whether a subject’s pain sensitivity predicts acute postoperative pain, there is better evidence that enhanced pain sensitivity contributes to the development of persistent postoperative pain (Granot 2009). Some preoperative psychosocial factors, such as attitude and mood, appear to be more important than others in promoting surgical recovery (Rosenberger et al 2006). In particular, high catastrophizing has been found to be associated with increased postoperative pain severity and an increased incidence of the development of chronic pain (Khan et al 2011). In fact, in examining factors that contribute to poor pain outcomes at 6 months after total knee arthroplasty, preoperative pain catastrophizing was the only psychological measure that predicted poor outcomes (Riddle et al 2010).

Acute Postoperative Factors

Intraoperative nerve injury is believed to be a likely causal mechanism in the development of persistent postoperative pain (Katz and Seltzer 2009). This may explain the high incidence of chronic pain after hernia repair or thoracotomy, two procedures that involve cutting or compression of nerves. Surgical trauma induces neuroplastic changes in pain sensitivity such that mechanical hyperalgesia can be demonstrated both in the area of inflammation (primary hyperalgesia) and in the non-inflamed surrounding tissue (secondary hyperalgesia). Studies have used a technique to measure the area of punctate mechanical hyperalgesia surrounding surgical wounds during the acute postoperative period (Stubhaug et al 1997, Lavond’homme et al 2005), and this may predict which patients will have persistent postoperative pain. Many studies have shown that the intensity of acute postoperative pain is a predictive factor for the development of persistent postoperative pain (Kehlet et al 2006). After breast surgery, clinically meaningful acute postoperative pain independently predicted more intense chronic pain 3 months after surgery (Poleshuck et al 2006).

Epidural Analgesia

Achievement of optimal results with a continuous epidural analgesia technique requires appropriate perioperative planning and assessment. At the authors’ institution, epidural catheters for postoperative analgesia are commonly placed immediately before induction of operative anesthesia. This practice allows the anesthesiologist to administer a test dose of local anesthetic for evaluation while the patient is still awake. This facilitates the diagnosis of intrathecal, intravascular, or subdural catheter placement and allows confirmation of segmental epidural analgesia when the test dose of local anesthetic is administered. It also allows the continuous epidural infusion to be started during surgery.

This segmental nature of analgesia mandates the need to place an epidural catheter in a location to cover the dermatomes included in the surgical field. A general guideline for catheter locations in various types of surgeries is as follows: thoracic surgery—upper to lower thoracic; upper abdominal and renal surgery—low thoracic to high lumbar; orthopedic procedures of the lower extremities and lower abdominal and gynecologic surgery—lumbar region. Alternatively, catheter placement should be approximately at the dermatomal level that corresponds to a point intersecting the upper one-third and the lower two-thirds of the surgical incision. The differences among the opioids used for epidural analgesia relate to their duration of action and propensity to produce side effects. Patient factors such as advanced age, small body habitus, morbid obesity, history of sleep apnea, and general debilitation should be considered when initiating epidural analgesia because these conditions are associated with a greater propensity for respiratory complications. Reduced concentrations of opioids should be used when initiating epidural analgesia in such patients. Clonidine is used in patients who are taking opioids preoperatively.

Although epidural analgesia is usually effective, patients may occasionally experience inadequate pain relief. A systematic approach is necessary to evaluate and manage inadequate epidural analgesia. The initial step in this process is verification of the integrity of the catheter system, followed by a bolus (5–7 mL) of the epidural solution (typically a combination of dilute local anesthetic with opioid) and analgesic assessment after a short interval (15–30 minutes). If analgesia remains inadequate, a test dose of a local anesthetic solution, such as 2% lidocaine with 1:200,000 epinephrine, can then be given to evaluate the epidural catheter location. The test dose usually yields one of three results. If a bilateral sensory block occurs in a few segmental dermatomes, epidural catheter location is confirmed. In this case the volume of the infusion was probably insufficient for adequate dermatomal coverage, with resultant inadequate analgesia, and increasing the rate of infusion may produce effective analgesia. A unilateral sensory block after administration of a test dose of a local anesthetic is suggestive of the catheter tip residing laterally in or near a neuroforamen. Withdrawal of the catheter 1–2 cm is usually associated with a bilateral sensory block after a subsequent test dose. Once bilateral sensory blockade has been documented, adequate analgesia can be maintained with bolus administration of the epidural solution, followed by adjustment of the continuous epidural infusion or patient-controlled epidural infusion parameters.

Finally, lack of sensory blockade after test dose administration indicates that the epidural catheter does not reside in the epidural space. In this situation, the catheter is removed and the patient is given the option of having another epidural catheter placed or switching to PCA therapy.

Improvements in Monitoring of Postoperative Pain (Numerical Rating Scales and Beyond)

Acute pain is a personal experience, and measurements should rely on recording the patient’s own report because it has been demonstrated that staff underestimates pain and overestimates treatment effects. A patient’s pain and response to treatment should be assessed regularly for several days, depending on the surgical procedure. Although great emphasis has been placed on improving pain in the first 24 hours with various nerve blocks or IV formulations, the major gap may be the transition process from this state to oral analgesics and continuous treatment after discharge from the hospital. Pain assessments should be recorded in a readily available and visible form, together with other vital observations. Monitoring of postoperative pain should reflect not only pain intensity at rest but also activity-associated, dynamic pain and treatment-induced side effects by using standardized methods and protocols. Pain during activity and side effects such as sedation, PONV, and dizziness may prolong rehabilitation and the need for hospital stay.

A number of measurement scales have been used and validated, including categorical scales and the visual analog scale (VAS). Categorical pain intensity scales use words to describe the magnitude of the pain—for example, “no,” “mild,” “moderate,” and “severe” pain. Pain relief scales most often use the descriptors “none,” “slight,” “moderate,” “good,” and “complete.” The VAS uses a 10-cm line with the left end labeled “no pain” and the right end labeled “worst possible pain,” and numerical rating scales-(NRS) of pain intensity asks people to rate their pain from 0 (no pain) to 10 (worst pain). Recent reviews comparing different pain intensity scales have concluded that the VAS and the numerical rating scale are preferred over categorical measures (Dworkin et al 2005, Breivik et al 2008).

Pain relief scales may be perceived as being more convenient than pain intensity scales, particularly in analgesic trials, because patients have the same baseline relief (zero) but could start with different baseline intensity. The approach most commonly used in the immediate postoperative period, at least after major surgical procedures, however, is the use of categorical or visual analogue pain intensity scales. This is due to the fact that most often analgesia is initiated before the patient is awake and thus no baseline relief can be assessed. Sophisticated questionnaires, such as the McGill Pain Questionnaire, may provide a more comprehensive description of the different elements contributing to postoperative pain, but the use of such questionnaires is seldom practicable in daily clinical practice or may not be useful in directing treatment.

The use of neuroimaging for assessment of pain has gained recognition for both acute pain (Iadarola et al 1998) and chronic pain (Apkarian et al 2011). It may also play a vital role in determining the sites of activation for acute postoperative pain (Buvanendran et al 2007).

Advantages of Patient-Controlled Analgesia

IV PCA has been an accepted standard for management of postoperative pain for more than 20 years (Viscusi 2008). The primary advantage of PCA is high patient satisfaction, although there may not be a difference in pain scores. One review found that PCA opioid analgesia produced greater patient satisfaction than did conventional parenteral “as-needed” analgesia, as well as better pain control, but patients using PCA consumed higher amounts of opioids and had a higher incidence of pruritus (Hudcova et al 2006). PCA has several drawbacks. Device safety, in particular, pump programming errors, is always of concern, and newer infusion systems have better software to reduce the incidence of medication errors (Viscusi 2008). In addition, there is still an issue with patient comfort and mobility since the patient is attached to the pump, IV line, and pole.

Procedure-Specific Pain Management

The Procedure-Specific Postoperative Pain Management (PROSPECT) plan provides procedure-specific information on evidence-based pain treatment in various common operations (Kehlet et al 2007).

Genetic Factors

Over the past 10 years a few genetic factors have been identified that are associated with human chronic pain syndromes (Kim et al 2009). However, no strong genetic association was found between monoamine neurotransmitter systems and acute postsurgical pain in patients undergoing oral surgery (Kim et al 2006). In addition, there are no published reports about genes that increase the risk for chronic postoperative pain (Katz and Seltzer 2009).

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