Phillip S. Owen, PharmD, BCPS

Data from large survey reports suggest that more than 80% of Americans who undergo surgery experience some level of postsurgical pain.

 Oral opioid analgesics represent the majority of medications used to treat postsurgical pain, and a high frequency of opioid-related adverse drug events (ORADEs) have been reported.

 Current data suggest that ORADEs are reported in more than 70% of inpatients.

Two studies analyzing the economic impact of ORADEs found that the cumulative cost ranged from $400,000 to $1.3 million over a 5-year and a 10-year study period, respectively.

These facts have driven the pursuit of evidence-based therapeutic approaches and formulation of guidelines for pain practitioners.

Acute postsurgical pain management evolved rapidly throughout the 1980s in the United States, propelled mainly by research on opioid pharmacology from the previous decade.

 Prior to such knowledge, most mild to moderate pain was treated with either acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), and moderate to severe pain was treated with intermittent opioids. The introduction of intravenous infusion pump technology for patient-con- trolled analgesia (PCA) and neuraxially administered opioids has led to significant changes in pain management in clinical practice.

 In addition, recent research findings have helped shape pain management protocols in special populations, such as the elderly, obese individuals, patients with obstructive sleep apnea, and those with preoperative chronic pain issues.

The most recent literature surrounding postsurgical pain control describes 3 main phases of care for surgery patients and the therapeutic interventions applied in each phase. The first phase, the pre- operative therapeutic phase—also called preemptive analgesia or preventive analgesia&mdash;has been the most clinically controversial and disputed of all the perioperative pain management phases.

 With preemptive analgesia, preventive therapeutic interventions are directed at decreasing the central sensitization of pain that is elicited by noxious input from the eventual surgical procedures that could lead to chronic postoperative pain.

 The shared belief among clinicians and basic scientists is that the nociceptive afferent fibers in the periphery, and those that act centrally at the level of the spinal cord, are augmented by nociceptive mediators that lead to hypersensitivity and hyperexcitability and induce a state of hyperalgesia that could be perpetuated long into the post- operative course, creating a chronic postoperative pain syndrome.

The specific preventive agents that have been researched in clinical trials include NSAIDs, anxiolytics, and anticonvulsants (Online Table 1

). From what study results have shown, ketorolac and gabapentin have yielded positive results in terms of reducing patient- reported pain and opioid consumption when administered preoperatively.

 Interestingly, the preoperative use of nonselective NSAIDs (eg, ketorolac, ibuprofen, naproxen) has been more effective in augmenting pain and pro- viding a safer alternative to the more selective anti-inflammatory agents (eg, cyclooxygenase-2 inhibitors such as celecoxib). The latter group of NSAIDs may pose more cardiovascular risk, especially in patients who may have cardiovascular comorbidities (eg, coronary artery disease, diabetes, cerebrovascular disease).

Gabapentanoids offer a unique mechanism of action, distinct from NSAIDs or opioids, that provides added dimension to multimodal pain control.

 Specifically, data show that preoperative oral gabapentin provides better pain control than pregabalin despite the fact that pregabalin has faster absorption and better oral bioavailability.

 Both agents have more reported central nervous system effects when used with other pain therapies in a multimodal fashion, but there is consensus that these agents may help with decreasing chronic postsurgical pain when administered preoperatively.

 An additional agent that has some preoperative use is low-dose (<1 mg/kg or 10 mcg/kg/ hr) ketamine when used in conjunction with other analgesics, local anesthetics, parenteral opioids, and/or epidural opioids.

Ketamine is a noncompetitive N-methyl-D-aspartate inhibitor that not only provides analgesia, but may even reduce the occurrence of opioid-induced

hyperalgesia which is becoming more characterized in the literature.

Single-dose neuraxial administration and peripheral nerve block therapies could be an option for limiting opioid-induced delay of mobilization and physical rehabilitation; however, this requires preoperative catheter placement and specialized intraoperative and postoperative management, and a risk— benefit assessment is necessary to avoid complications with other medications (eg, anticoagulants, antiplatelets).

 In addition, neuraxial analgesia, in the form of epidural analgesia, has several disease-state contraindications (eg, valvular disease, compromised left ventricular outflow, hypovolemia, delirium) that make it a more high-risk component of the multimodal approach. Therefore, epidural analgesia must be individualized on a case-by-case basis.

Intraoperative analgesic formulations and techniques encompass the afore- mentioned neuraxial epidural and spinal analgesia interventions, as well as peripheral nerve blocks and several other potential intravenous products. Intravenous lidocaine, ibuprofen, acetaminophen, and local wound infiltration have all been studied in the intraoperative setting. Systemic, continuous lidocaine infusion has had limited benefit, in all but abdominal surgery patients in whom it showed improvement on pain intensity and opioid consumption, as well as return of bowel function.

 Intravenous acetaminophen and ibuprofen could be potential adjuncts with opioids analgesics.

The benefit of pain control with these agents is somewhat offset by their acquisition costs relative to other traditional agents. Specifically, the pharmacoeconomics of intravenous acetaminophen has been discussed in the literature.

 The conclusion drawn from such analysis usually depends on the reader’s familiarity with pharmacoeconomic analytics and the ability to surmise a willingness- to-pay tolerance that is needed when contemplating formulary management issues.

Likewise, local wound infiltration using new and old formulations of local anesthetics has shown decreased

opioid consumption and pain scores, but diverse study design has been a limitation of these analyses.

The newer formulation of liposomal bupivacaine has also gained attention recently for its long duration of action that suggests a more profound reduction in opioid consumption and pain perception over 72 hours. As with intra- venous acetaminophen and ibuprofen, however, the liposomal formulations of bupivacaine are costly compared with the nonliposomal formulations; thus, a more in-depth review of cost versus benefit is required.

The postoperative phase is usually one in which neuraxial analgesia (mostly in the form of epidural analgesia) or intravenous opioid therapy transitions to oral opioid therapy or a combination of oral and PCA opioid therapy. Data on epidural analgesia in the postoperative setting have consistently shown a reduction in systemic opioid consumption, pain intensity scores, time to rehabilitation, and overall incidence of perioperative morbidity.

The overall effect of epidural analgesia on perioperative mortality is unclear.

 PCA has developed concurrently with previously mentioned interventions as infusion pump technology has advanced. Data on PCA have shown, with high consistency, that it offers patients a sense of autonomy with controlling their own pain.

 This perceived benefit has translated to higher patient satisfaction scores in most studies as well.

 Given the health care climate, patient satisfaction has become a huge factor in determining treatment choice, especially when adequate pain control is a large factor for hospitals maintaining compliance with mandated treatment standards.

The last postoperative intervention usually entails conversion to a reliable oral opioid regimen. The transition to commonly used oral opioids (Table 2

) from intravenous therapy in the postoperative setting helps to facilitate oral intake, assess patient tolerance to a regular diet, and further assess patient discharge readiness with an oral pain control regimen. Many therapeutic challenges arise when providers start converting from intravenous to oral opioid doses to meet baseline and break- through pain control needs.

 Many resources exist to aid the provider in making safe conversions, but no one resource is completely adequate in guaranteeing safe conversion back and forth across dosage forms and among different opioid agents.

 Thus, the advent of acute pain services (APS) has been key in providing skilled knowledge, not only on structuring multimodal pain control strategies, but also offering recommendations on the transition from one opioid dose form to another, as well as within opioid classes.

Special populations that have specific needs or comorbidities, beyond the average surgical patient, are best managed by a multimodal pain therapy approach. The special populations include patients who are elderly or obese, as well as patients who have obstructive sleep apnea, chronic pain, or opioid tolerance. These patients require individualized therapy using combinations of the different analgesic medications and techniques discussed here to optimize control and reduce the risk for adverse events.

 Furthermore, the implementation of APS will aid in facilitating an appropriate patient-focused multimodal analgesic plan and serve as a liaison with the patient’s pain needs and the rest of the health care team.

With the trend in creation of inpatient APS, clinical pharmacists have an opportunity to collaborate with other health care workers to optimize multimodal pharmacotherapy outcomes within the existing formulary of their institution, reduce the potential for ORADEs, and minimize the risk for chronic postoperative pain syndrome to develop into a new chronic comorbidity after surgery. Clinical pharmacists also have the potential to lead the educational needs regarding opioid therapy conversions and disseminate new information on PCA pump technology, combination epidural products, and anesthetic infiltration products. This initiative could allow pharmacists to have a greater impact on clinical practice, medication safety, and formulary management.

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Dr. Owen is a cardiothoracic intensive care unit pharmacist for the Thoracic & Vascular Surgery Services, University of North Carolina Medical Center Lung Transplant Team. 

Phillip S. Owen, PharmD, BCPS

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