Postoperative Pain and Its Management

Benefits

μ-Opioid agonists (e.g., morphine) have been the mainstay in the management of moderate to severe postoperative pain for the past hundred years. They directly interact with the most powerful endogenous pain-reducing system of the body. Commercially available analgesic opioids cross the blood–brain barrier and act in both the brain and spinal cord. Opioids can also be administered epidurally or occasionally intrathecally to control postoperative pain while reducing systemic exposure.

A wide choice of opioids are available for management of postoperative pain: morphine, hydromorphone, fentanyl, sufentanil, buprenorphine, meperidine, hydrocodone, and oxycodone. Long-acting opioids have the advantage of providing a steady plasma level of the narcotic, thereby preventing the wide fluctuations in plasma levels that can lead to inconsistent analgesia. However, proper timing and dosing of the long-acting opioids are critical to obtain the optimal patient outcome.

Side Effects

The main side effects of opioids in the postoperative setting are gastrointestinal, including postoperative nausea and vomiting (PONV), ileus, and constipation; urinary retention; pruritus; central nervous system effects, including sedation and somnolence; and respiratory depression ( ). In a comparison of three opioids administered intravenously via patient-controlled anesthesia (PCA), fentanyl produced fewer adverse reactions and lower pain scores than did morphine or hydromorphone ( ). No difference was found in the quantity of opioid used when converted to equivalence. In determining the dose and drug for PCA, it is critical to examine the pharmacokinetics of the therapeutic agent. Intravenous (IV) opioids that have a short half-life may require a continuous infusion to maintain a steady plasma level in addition to the PCA mode. However, extreme caution needs to be exercised before continuous modes of opioids are administered via PCA to patients at high risk, such as those prone to sleep apnea or patients with a compromised respiratory system.

Opioid-Induced Hyperalgesia

A problem with opioid use that has recently caused some concern is opioid-induced hyperalgesia (OIH; , ). In addition to studies of this phenomenon in animal ( ) and human experimental models, some clinical trials have also shown that perioperative opioids can increase postoperative pain or postoperative opioid consumption ( ). Therefore, even though opioids are deemed to be the “gold standard” for management of postoperative pain, paradoxically they may also facilitate postoperative pain in humans following abdominal and orthopedic surgery. Furthermore, there appears to be a positive relationship between the intraoperative opioid dose and the postoperative opioid requirement ( ). Consequently, what appears to be short-term tolerance to an opioid may not in fact be due to a decrease in its efficacy (pharmacological tolerance) but rather be a result of enhanced pain sensitivity (OIH) as manifested by an apparent decrease in the effectiveness of morphine. Distinguishing between these two phenomena has significant implications for the management of postoperative pain. If rapid escalation of the opioid dose in the immediate postoperative period fails to provide beneficial effects, one must consider the possibility of OIH. If the latter cause is suspected, a reduction in the opioid dose or switching to an alternative opioid (opioid rotation) may be beneficial. Moreover, the use of adjuvant drugs should also be considered because they not only contribute to an opioid-sparing effect but may also potentially result in a reduction in OIH. Knowledge in this area is just beginning to emerge, and the current information is not sufficient to propose new guidelines for the use of opioids in the postoperative period.

Opioids and Sleep Apnea and Monitoring

First recognized 35 years ago, an estimated 18 million Americans have obstructive sleep apnea (OSA). Of the people suffering from OSA, it is estimated that it is undiagnosed in 80–90%. Obesity (body mass index >29 kg/m²) has been found to be strongly associated with OSA ( ). A known or presumptive diagnosis of OSA in a patient scheduled for surgery can influence postoperative analgesic management. Hence it is recommended that a history of nocturnal snoring and/or apnea and a history of daytime sleepiness be sought routinely in every obese adult patient preoperatively ( ), in addition to evaluating a scoring system to determine whether OSA is present per recommendations of the . Patients with OSA are particularly sensitive to the depressant effects of opioids, sedatives, and tranquilizers. Opioids have been shown to increase sleep and decrease arousal mechanisms. In a patient without OSA, the hypoxemia and hypercapnia that ensue following the use of opioids and other sedatives trigger the carotid chemoreceptors and the respiratory receptors of the brain stem to increase respiratory drive. However, in individuals with OSA, this protective physiological response is particularly vulnerable to the effects of opioids and other sedatives. Therefore, in these individuals, it is recommended that opioid analgesia be avoided and a multimodal analgesic regimen that includes regional analgesia be used during the postoperative period. In addition, it is important that patients continue their continuous positive airway pressure settings during the perioperative period and that oxygen saturation be monitored more frequently.

Respiratory Depression and Opioids

The Anesthesia Patient Safety Foundation (APSF) believes that clinically significant drug-induced respiratory depression (oxygenation and/or ventilation) in the postoperative period remains a serious patient safety risk factor that continues to be associated with significant morbidity and mortality. The APSF came to the following conclusions and recommendations reflecting the majority opinions (consensus): “Future technology developments may improve the ability to more effectively utilize continuous electronic monitoring of oxygenation and ventilation in the postoperative period. However, maintaining the status quo while awaiting newer technology is not acceptable.” Intermittent “spot checks” of oxygenation (pulse oximetry) and ventilation (nursing assessment) are not adequate to reliably recognize clinically significant evolving drug-induced respiratory depression in the postoperative period. Continuous electronic monitoring of oxygenation and ventilation should be available and considered for all patients and would reduce the likelihood of unrecognized clinically significant opioid-induced depression of ventilation in the postoperative period. Continuous electronic monitoring should complement and not replace traditional intermittent nursing assessment and vigilance. All patients should have their oxygenation monitored by continuous pulse oximetry. Capnography or other monitoring modalities that measure the adequacy of ventilation and airflow are indicated when supplemental oxygen is needed to maintain acceptable oxygen saturation. Although careful preoperative screening for conditions that may be associated with increased risk for postoperative respiratory insufficiency (OSA, obesity, chronic opioid therapy) is recommended and may be part of a graduated continuous monitoring adoption plan, applying electronic monitoring selectively based on perceived increased risk is likely to miss respiratory depression in patients without risk factors. Continuous monitoring of oxygenation and ventilation from a central location (telemetry or comparable technology) is desirable. This information needs to be reliably transmitted to the health care professional caring for the patient at the bedside. Structured assessment of the level of sedation or consciousness is a critical component of the nurse’s routine postoperative patient assessment for detecting respiratory depression. Nurse and physician education is critical to ensure an understanding of the physiology and pharmacology of drug-induced respiratory depression, the potential obscuring impact of patient arousal on respiratory depression during clinical assessment, and the interference of supplemental oxygen administration on detection of progressive hypoventilation when pulse oximetry is the only continuous electronic monitor. Continuous electronic monitoring systems should integrate multiple physiologic parameters to identify clinically significant changes earlier and more reliably. The APSF is aware of hospital systems that have adopted continuous capnography in combination with pulse oximetry—or in lieu of pulse oximetry. The APSF acknowledges that because of limited health care resources, implementation of these conclusions and recommendations may be part of a graduated continuous electronic monitoring adoption plan. However, institution of these conclusions and recommendations must not be delayed while awaiting newer technology. The APSF advocates increased public and private investment in research to develop monitors with high reliability and ease of use. The APSF believes that multimodal analgesia techniques need to be used more often to decrease the use of opioids alone for management of postoperative pain.

NSAIDs and Cox-2–Selective Inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) are a diverse group of compounds with analgesic, antipyretic, and anti-inflammatory activity. Today, NSAIDs are the most widely prescribed drugs in the world, with sales in excess of $2 billion in the United States and $6–8 billion worldwide. Prostaglandins, including prostaglandin E ₂ (PGE ₂ ), are responsible for reducing the pain threshold at the site of injury (peripheral sensitization). The primary site of action of NSAIDs is believed to be in the periphery, although recent research indicates that central inhibition of Cox-2 may also play an important role in modulating nociception ( ). NSAIDs inhibit the synthesis of prostaglandins, thus diminishing the hyperalgesic state after surgical trauma. NSAIDs are useful as the sole analgesic after minor surgical procedures and may have a significant opioid-sparing effect after major surgery. Recent practice guidelines for management of acute pain in the perioperative setting specifically state that “unless contraindicated, all patients should receive around-the-clock regimen of NSAIDs, COX-2 inhibitors, or acetaminophen” ( ).

A parenteral formulation of ketorolac tromethamine has been available for many years for the treatment of postoperative pain. As with any mixed Cox-1/Cox-2 inhibitor, the primary concern is the increased postoperative bleeding that has been documented for NSAIDs as result of their Cox-1 component ( ). Other injectable NSAIDs such as ibuprofen (just approved in the United States) are also becoming available. Postoperative patients who have ileus and when bleeding is not a concern may benefit from the injectable NSAID formulations. Newer NSAID injectables are currently in the final phases of clinical trials.

Unlike other NSAIDs, Cox-2–selective inhibitors, when used in the perioperative setting, have the advantages of not increasing the risk for bleeding and fewer gastrointestinal side effects. However, concern for adverse cardiovascular events with chronic use has resulted in the elimination of Cox-2–selective inhibitors, except celecoxib, from the United States. Despite the favorable reports on celecoxib versus placebo for management of postoperative pain ( , ), most patients were still dependent on rescue opioids. Celecoxib should therefore be considered as part of a multimodal anesthesia protocol.

Rofecoxib is a Cox-2–selective inhibitor that is no longer used because of adverse cardiovascular events. However, biochemical data obtained during clinical trials in which rofecoxib was given orally before joint replacement surgery revealed the mechanisms by which Cox-2 inhibition reduces postoperative pain ( ). Following total hip arthroplasty in the placebo group, PGE ₂ increased at the peripheral site (hip drain), but in the rofecoxib groups, hip drain PGE ₂ was reduced. In addition, hip drain PGE ₂ was positively correlated with poorer functional recovery. Cerebrospinal fluid (CSF) PGE ₂ also increased in the placebo group after surgery, whereas it was decreased in the rofecoxib group. As in the case of hip drain fluid, CSF PGE ₂ was also positively correlated with the intensity of postoperative pain.

Acetaminophen (Paracetamol): Oral and Intravenous

Acetaminophen (paracetamol) does not have peripheral anti-inflammatory activity but acts centrally to reduce PGE ₂ and fever. Moreover, it has analgesic properties and fewer side effects than NSAIDs do. Oral acetaminophen has been available for postoperative pain management for more than a century. Greater use is now being made of IV acetaminophen as an analgesic for many surgical procedures ( ). IV acetaminophen provides more predictable bioavailability and has a predictable onset when compared with enteral routes of administration. However, hepatotoxicity associated with aniline derivatives is a concern. IV acetaminophen is the first in the class of IV non-opioid, non-NSAID analgesics currently in use in the United States and became available in 2010. IV acetaminophen has been demonstrated to be a safe and efficacious parenteral analgesic agent across a wide array of postoperative settings, from minor outpatient to complicated or major inpatient surgery. It has the potential to provide significant therapeutic improvement in the treatment of fever and acute postoperative pain. There appears to be much benefit to incorporating acetaminophen as part of a multimodal analgesia regimen.

Gabapentoids (Gabapentin, Pregabalin)

Use of anticonvulsants that bind to the α ₂ δ subunit of voltage-gated calcium channels, the gabapentoids, has increased in the past decade for many types of chronic pain, and it is starting to be used in postoperative pain settings ( ). Pregabalin has been shown to have a more favorable pharmacokinetic profile than gabapentin, including increased bioavailability, longer half-life, and increased potency ( ).

NMDA Antagonists (Ketamine, Memantine, Dextromethorphan, Magnesium)

Because l -glutamate is the most important excitatory neurotransmitter in the central nervous system, blocking glutamate receptors offers an attractive method of reducing afferent stimulation of the spinal cord and therefore blocking pain transmission ( ). In particular, many drugs or compounds that reduce central glutamate excitation are antagonists of the N -methyl- d -aspartate (NMDA) subtype of glutamate receptor. Although there are two other ion-gated glutamate receptor subtypes, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainite receptors, as well as G protein–coupled glutamate receptors, none of these pharmacological subtypes are represented by drugs in clinical use for pain.

Ketamine, a non-competitive NMDA antagonist, has been used as a general anesthetic and analgesic for the past three decades. It has demonstrated some analgesic or anti-hyperalgesic potential in a large number of clinical trials of postoperative pain, although it has generally been used as an adjuvant medication to opioids, local anesthetics, or other analgesic agents ( , , ). High doses of ketamine have been implicated in causing psychomimetic effects (excessive sedation, cognitive dysfunction, hallucinations, nightmares), but subanesthetic or low doses of ketamine have demonstrated significant analgesic efficacy without these side effects. Low-dose ketamine has not been associated with adverse pharmacological effects on respiration, cardiovascular function, nausea, vomiting, urinary retention, and constipation/prolonged adynamic postoperative ileus. An IV bolus at the beginning of surgery followed by a 24-hour infusion decreased morphine consumption in patients undergoing total hip arthroplasty ( ). More interestingly, patients receiving ketamine had a decreased incidence of chronic pain. At 6 months, 21% of placebo- and 8% of ketamine-receiving patients had persistent pain. Similar results have been found by others, albeit in opiate-dependent patients undergoing lumbar spine surgery ( ). A ketamine infusion of 10 μg/kg/min was started at the beginning of surgery after a bolus of 0.5 mg/kg was administered and terminated at skin closure. Significant results included decreased postoperative morphine requirements and lower pain scores 6 weeks postoperatively.

Memantine was first synthesized in the 1960s and found to antagonize the NMDA receptor in the 1980s. It is completely absorbed from the gastrointestinal tract with maximal plasma concentrations occurring between 3 and 8 hours after oral administration. Approximately 80% of the dose administered remains as the parent drug. Its mean terminal elimination half-life is 60–100 hours. Although memantine does not appear to be beneficial as an analgesic therapy for long-term established chronic neuropathic pain, it may be a useful adjunct when used early in specific settings such as the initial phases of phantom limb pain or soon after surgery on opioid-tolerant subjects ( ). Ketamine causes memory deficits, reproduces with impressive accuracy the symptoms of schizophrenia, is widely abused, and induces vacuoles in neurons at moderate concentrations and cell death at higher concentrations. Memantine, in contrast, is well tolerated; although instances of psychotic side effects have been reported, in placebo-controlled clinical studies the incidence of side effects is remarkably low.

Dextromethorphan and its metabolite dextrorphan have been found to antagonize NMDA receptors in brain slices ( ). Although dextromethorphan is an open-channel blocker similar to ketamine, it produces fewer psychotomimetic effects, probably because of its lower affinity for the NMDA receptor ( ).

α ₂ -Adrenergic Agonists (Clonidine, Dexmedetomidine)

In addition to the opiate system, α ₂ -adrenergic activation represents an inherent pain control network of the central nervous system. α ₂ -Adrenergic receptors are abundant in the substantia gelatinosa of the dorsal horn in both rats and humans and appear to be the primary site of action where α ₂ -adrenergic agonists can inhibit somatic pain ( , ). This receptor system also exists in the brain, where its activation can produce sedation. Cardiovascular depression from α ₂ -adrenergic agonists can occur at both brain and spinal cord sites ( ). These side effects of sedation and sympathetic inhibition limit the use of α ₂ -adrenergic agonists to just an adjuvant role as analgesics.

Clonidine was originally used to control blood pressure and heart rate. However, it is now known that it also has antinociceptive properties in both rodents and humans. Clonidine binds to α ₂ -adrenergic receptors in the central nervous system, as well as to imidazoline receptors in the brain ( ). It has been hypothesized that clonidine acts at α ₂ -adrenergic receptors in the spinal cord to stimulate the release of acetylcholine, which acts at both the muscarinic and nicotinic subtypes for postoperative pain relief ( ). Clonidine has been administered by various systemic routes as an adjuvant to reduce postoperative pain: orally, intravenously, and as a transdermal patch. The results of such studies have been mixed. Better results were observed when clonidine was added as an adjuvant to epidural analgesics or to local anesthetics for PNB.

Since its approval for clinical use, dexmedetomidine has been used for sedation during surgery and in the postoperative period. Dexmedetomidine is an α ₂ -adrenergic agonist with even better selectivity for that receptor than clonidine has ( ). For postoperative pain control, it is primarily used as an IV adjuvant to opioids.

Glucocorticoids

There is a long history of using glucocorticoids to reduce inflammation and postoperative pain in many surgical procedures ( ). Glucocorticoids (corticosteroids) are steroids that bind with high affinity to the glucocorticoid receptor in the cytosol of cells. There are multiple sites of action at which glucocorticoid-activated receptors produce anti-inflammatory and immunosuppressive effects ( ). However, the powerful anti-inflammatory nature of corticosteroids, through inhibition of prostaglandin synthesis, may also have detrimental side effects with high or repeated dosing.

Dexamethasone is a synthetic glucocorticoid with high potency and a long duration of action (half-life of 2 days), but it has no mineralocorticoid activity. Prostaglandins are one of the main inducers of inflammation after tissue injury, and one of the mechanisms by which glucocorticoids reduce prostaglandin synthesis is by inhibiting the expression of Cox-2 ( ). Studies using dexamethasone for postoperative pain relief have produced mostly positive results, especially with surgical procedures involving a large amount of tissue trauma, such as orthopedic and neurological surgery ( ). A recent review concluded that a single preoperative IV dose of dexamethasone (4–8 mg) reduces postoperative pain after ambulatory surgery ( ). In a meta-analysis of perioperative dexamethasone, preoperative administration of dexamethasone produced a more consistent analgesic effect than intraoperative administration did ( ). In addition to reducing inflammation, dexamethasone can also reduce PONV.

Acetylcholine Esterase Inhibitors (e.g., Neostigmine) and Cholinergic Drugs (e.g., Nicotine)

Acetylcholine esterase inhibitors and muscarinic receptor agonists increase pain thresholds ( ). Muscarinic receptors occur at high density in the superficial dorsal horn, and it is hypothesized that nearby cholinergic neurons stimulate these receptors to reduce postoperative pain ( ). Acetylcholine may cause analgesia through direct action on the M ₁ and M ₃ spinal cholinergic muscarinic receptor and nicotinic receptor subtypes and indirectly through stimulation of release of the second messenger nitric oxide in the spinal cord.

The acetylcholinesterase inhibitor neostigmine, when administered systemically, cannot access spinal cord cholinergic receptors because the compound does not cross the blood–brain barrier. However, intrathecal and epidural administration of neostigmine provides effective postoperative analgesia. Its clinical use, however, is limited by significant side effects, in particular, nausea, vomiting, and sedation ( , ).

Neuronal nicotinic acetylcholine receptors are ligand-gated ion channels. Agonist activation allows cations to enter the cell. Nicotine is a classic agonist at these receptors, and newer nicotinic compounds such as epibatidine have been studied in pain models. However, even with intrathecal administration to limit systemic side effects (e.g., adverse effects on autonomic function), these agonists do not produce consistent analgesia ( ).