In 1963, Roe¹ was the first to manage postoperative pain by titrating small intermittent intravenous (IV) boluses of morphine at intervals of 10-30 minutes, until it was apparent that adequate relief was obtained.² He found that small IV doses of opioids provide more effective pain relief than conventional intramuscular (IM) injections. Roe described the widely differing analgesic requirements among postoperative patients. The first attempt at patient controlled analgesia (PCA) was described by Sechzer in 1968.³ Sechzer, known as the true pioneer of PCA, evaluated the analgesic response to small IV doses of opioid administered according to patient demand by a nurse in 1968 and then by machine in 1971.² Though theoretically a great study, it was impractical for clinical practice to provide multiple and frequent administration of IV doses of opioid by nurses to large numbers of patients. Since that time, PCA devices have evolved enormously in technological sophistication.

PCA is a conceptual framework for administration of analgesics² (Fig. 33.1). The broader concept of PCA is applicable to any analgesic given by any route of delivery; it can be considered PCA if administered on immediate patient demand in sufficient quantities.² An ideal PCA system has many advantages⁴ and demonstrates efficacy for a variety of surgeries, ease of preparation, maintenance, and administration, with minimal technology-related complication. Additionally important is the safety profile of the analgesic given while optimizing patient comfort and satisfaction.⁵ An ideal system minimizes analgesic gaps by providing immediate dosing upon patient activation, providing uniform analgesia, and thereby reducing painful waiting periods.⁵ Less commonly discussed, yet still desirable, is the compatibility with overall current clinical care-encompassing treatments like physician therapy and antithrombotic therapy.⁵

PCA systems offer advantages over traditional intermittent dosing approaches of postoperative pain management.⁴ PCA methods optimize analgesic efficacy by allowing the patients to determine their need and dose frequency offering an inherent level of comfort and safety in the form of a physiologic negative feedback loop.⁵ A patient who is sedated will not choose to deliver additional doses of medication, thus, minimizing overdoses. PCA doses are typically smaller than bolus doses administered by nurses, which may improve the side effect to benefit ratio.⁵ Interestingly, PCA is associated with a higher total dose of opioid, yet it is not associated with increased risks of dangerous side effects.⁶

In general, PCA improves pain control and patient overall satisfaction.⁶

New PCA technologies include “smart” IV-PCA infusion pumps, needle-free options, such as the fentanyl HCl iontophoretic transdermal system (ITS), and PCA devices made for intranasal delivery.⁵ The sufentanil sublingual tablet system is another example of a newer PCA system that works by buccal delivery of opioids. Newer technologies like smart IV infusion
pumps can help reduce the incidence of medication errors by providing decision support to assist with proper dosing.⁵

The most common PCA system is administered intravenously; however, an analgesic can be delivered by other routes (epidural, peripheral nerve catheter, subcutaneous, intranasal, or transdermal) under patient control.⁴ The combination of multiple nonopioid analgesics with opioids delivered by PCA presents advantages over opioids alone.⁴ Morphine, hydromorphone, and fentanyl are some of the most common agents for PCA.⁶ This chapter will cover all of the current modalities of PCA and drug combinations available as well as the ongoing areas of research for future methods of PCA to better treat acute pain.

Austin deserves credit for first elucidating the pharmacologic principles that are the basis for intravenous patient-controlled analgesia (IV-PCA).² To demonstrate the steepness of the concentration-effect curve from opioid analgesics, they administered small increments of meperidine, measured plasma concentrations, and assessed patient pain scores² until the minimum effective analgesic concentration (MEAC) is achieved, which marks the difference between severe pain and analgesia.² Two prerequisites for effective opioid analgesia were thus established: (1) individualize dosage and titrate to pain relief response to achieve the MEAC and establish analgesia, and (2) maintain constant plasma opioid concentrations to avoid peaks and troughs.² These requirements cannot be achieved with as-needed or around-the-clock IM injections. After titrating to achieve the MEAC and establish analgesia, patients use PCA to maintain plasma opioid concentrations at or just above their individual MEAC, also known as the “optimal plasma concentration.”²

The benefits of IV-PCA in comparison to intermittent IM injection delivery of opioids have been best summarized in two published systematic reviews.² Both of these evidence-based reviews concluded that IV-PCA offers better analgesic efficacy, as well as superior patient satisfaction to IM injection. Although there is no evidence to support reduced opioid consumption or a difference in opioid-related side effects, Walder et al.⁷ concluded that PCA reduces postoperative pulmonary complications.²

In an IV-PCA system, the patient initiates an activation button attached by a cord to a PCA pump. A small dose of opioid is delivered to the patient from the IV line to an indwelling catheter.⁵ Dosing is controlled by a staff-programmed PCA pump. For all modes of PCA, there are the following basic variables: initial loading dose, demand dose, lockout interval, background infusion rate, and 1-hour and 4-hour limits. The two most common modes of PCA
are demand dosing, which is a fixed-size dose that is intermittently self-administered, and continuous infusion plus demand dosing, a constant-rate fixed background infusion supplemented by patient on-demand dosing.² The latter is also known as a basal infusion rate, which is a constant infusion rate regardless of whether the patient activates demand doses. Basal infusion PCA is generally not appropriate due to increased risk of overdose and respiratory depression. Additionally, when a background infusion is used with IV-PCA in opioid-naive patients, the incidence of respiratory depression is frequent.² However, a basal infusion can be implemented in those opioid-dependent or opioid-tolerant patients to replace a patient’s baseline opioid requirement. The basal dose can be calculated based on the opioid equivalence of the patient’s total daily chronic opioid and then is reduced by 30%-50%.⁶ Dosing is controlled by a programmed PCA pump, which is adjustable by trained staff and a lockout interval enforced to prevent excessive dosing.⁵

The initial loading dose allows for titration of medication when activated by the programmer prior to initiation of the medication to the patient. It can be used by postanesthesia care unit staff to titrate opioids to the MEAC or to give “breakthrough” doses. To prevent overdose by continual demand, all PCA devices use a lockout interval (or delay), which is the length of time the device will not administer another demand dose after a successful patient demand dose has been delivered, even if the patient continues to push the demand button.² The lockout interval is designed to prevent overdose. Ideally, it should be long enough for the patient to experience the maximal effect of one dose before another is permitted. Therefore, speed of onset of analgesia is paramount in setting the lockout interval. Based on this rationale, one might consider using a slightly shorter lockout interval when using the “fentanyl family of opioids” compared to morphine or hydromorphone.² Whichever opioid is chosen for IVPCA, knowledge of its pharmacology is a prerequisite for setting the dosing variables of the PCA device. Individual patient characteristics such as age, gender, and body weight are often assumed to be important factors influencing any pharmacologic therapy. Age affects opioid dosing, whereas gender and body weight do not.

Generally speaking, IV-PCA offers rapid analgesia, without the effects of first-pass metabolism with the goal of adequate titration in order to minimize the peaks and troughs in serum concentrations associated with clinician-controlled analgesia.⁵ Morphine, fentanyl, and hydromorphone are the most common agents used for IV-PCA.⁵ Tramadol is used extensively for IV-PCA in some European countries.² Although meperidine was the initial drug used to discover PCA, modern medicine has concluded meperidine for IV-PCA invites adverse outcomes in some patients while offering no advantage over alternative opioids.² Meperidine metabolites have greater seizure potential when combined with certain drugs. Hydromorphone and morphine IV-PCA remain the “gold standard” as the most studied and most commonly used IVPCA drugs in the United States. It is important to note that morphine has an active metabolite via glucuronidation—morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G produces analgesia, sedation, and respiratory depression. Prolonged and delayed onset of respiratory depression has been reported in patients with renal failure receiving parenteral morphine.² Therefore, it is recommended to avoid morphine for IV-PCA in patients with serum creatinine 2.0 mg/dL.² The more potent hydromorphone may have the best pharmacologic profile with similar onset and duration of action to morphine, but with decreased pruritus and nausea, and the absence of active metabolites.² Because of its lipophilicity, fentanyl has a quicker onset than morphine, perhaps making it better suited for IV-PCA; however, the rapid redistribution half-life of fentanyl results in a short duration of effect.²,⁶

Overall, IV-PCA is associated with high patient satisfaction.⁵ PCA is used to sustain comfort, allowing the patient to self-administer enough drugs to achieve a balance between analgesia and side effects.⁵ The common side effects of IV-PCA are the same side effects seen with opioid administration by any route or method of delivery; specifically, nausea and vomiting, constipation, pruritus, sedation, and, less commonly, respiratory depression and confusion.² Postoperative nausea
and vomiting (PONV) are the most common and most bothersome side effects of IV-PCA.² Anesthesia & Analgesia has published Consensus Guidelines for identifying and managing patients at risk of PONV associated with IV-PCA.⁸ Overall, small doses of pure opioid antagonists appear to be effective in reducing IV-PCA-related PONV and pruritus.² Although PONV is the most bothersome side effect to patients, respiratory depression is the most concerning for clinicians due to the potential sequelae of hypoxic injury as a result of opioid overdose.² An overall incidence for respiratory depression with IV-PCA can be estimated as 0.25%.

Nonpharmacologic drawbacks to IV-PCA involve the modality requiring an invasive indwelling catheter. The pump apparatus and accessories may limit patient mobility and thereby limit a patient’s level of comfort and access to performing activities of daily living while recovering in the hospital setting. IV line occlusions can lead to gaps in medication administration, catheter infiltration, needle-related injuries, and staff errors in programming administration are all potential downfalls associated with IV-PCA administration.⁵

There are significant benefits of a multimodal approach to acute pain management and IVPCA should not be considered a stand-alone therapy. Scheduled administration of NSAIDs clearly improves analgesia and reduces IV-PCA opioid requirements. Local wound infiltration, peripheral nerve blocks, and continuous catheter techniques can all be used effectively in conjunction with IV-PCA. Interestingly, a number of investigators have examined adding analgesic drugs directly to the IV-PCA mixture. These trials separately added ketamine and magnesium to morphine PCA and found that it significantly improved pain relief and reduced 24-hour cumulative morphine consumption.² These same investigators also found that adding small amounts of ketamine or magnesium to tramadol IV-PCA improved pain relief and reduced the amount of tramadol required after major abdominal surgery.² Ketamine clearly has an evolving role in acute pain management. However, caution and consideration of potential medication error should be evaluated before routinely adding it to an IV-PCA mixture.

Despite these disadvantages, IV-PCA is an accepted standard for acute postoperative pain management.⁵ Even though IV-PCA has a very acceptable safety profile, life-threatening mishaps do occur. Furthermore, there is no evidence to support a decrease in morbidity and mortality with IV-PCA, except perhaps some mild decrease in pulmonary complications.² It is clear that IV-PCA is inferior to epidural analgesia and other peripheral nerve block techniques for pain relief after severely painful surgical procedures.² Next, we will discuss the other modalities of PCA pain relief.

Though the traditional route of PCA delivery has been IV, patient-controlled epidural analgesia (PCEA) and patient-controlled regional analgesia (PCRA) are other modalities of PCA utilizing neuraxial routes that have been developed more recently.⁹

Patient-controlled epidural analgesia (PCEA) has most extensively been studied and used in the obstetric patient, as epidural analgesia is the most common modality and a highly effective way of providing safe labor analgesia.⁹,¹⁰,¹¹ A multicenter, randomized controlled trial found that IV-PCA and PCEA had the same rates of cesarean delivery or instrumental vaginal delivery, yet patients in the PCEA group reported better pain relief and satisfaction.¹¹,¹² Patients receiving IV-PCA had more adverse effects such as more sedation, more likelihood of antiemetic therapy, and more neonates requiring naloxone when compared to the PCEA group.¹¹,¹² In addition to labor analgesia, this mode of analgesia has also been effective in managing postoperative pain, including but not limited to patients who have undergone major operations such as abdominal, thoracic, or spinal surgery.

PCEA allows for individualization of analgesic requirements and a reduction in total opioid consumption with subsequent decrease in associated adverse systemic effects, a particularly attractive benefit in the setting of a current opioid crisis. Additionally, several studies suggest that PCEA compares favorably with use of traditional epidural analgesia delivered at a fixed rate, or continuous epidural infusion (CEI); with the added benefit of reduction in total local anesthetic dosing and attendant motor block.⁹

In variable scenarios, epidural analgesia has consistently demonstrated to be superior to IV-PCA and systemic opioids.¹³ A meta-analysis demonstrated that for all types of surgery and pain assessments, epidural analgesia including PCEA, provided superior postoperative analgesia when compared with IV-PCA.¹⁴ This was further supported in a systematic review of the analgesic efficacy of epidural analgesia.¹¹ Moreover, though satisfaction is a complex concept and difficult to measure, the improvement in postoperative analgesia and its benefits may contribute to greater patient satisfaction.¹⁵ PCEA is also regarded as a relatively safe and effective technique.¹⁵

Despite numerous investigations, the optimal PCEA analgesic solution and delivery parameters are not clearly defined. There are many combinations of PCEA parameters that can be classified using the following framework: (1) the type of infusion rate and (2) the infusion drug class. The type of infusion rate can be specified as a demand-dose alone, a continuous background infusion alone or a combination of both. This can be further classified by the infusion drug class as local anesthetic alone, opioid alone or a local anesthetic-opioid combination.

In contrast to IV-PCA, the use of a continuous infusion in addition to the demand dose, otherwise known as a background infusion, is routinely used for PCEA. It may provide analgesia superior to that of the use of a demand dose alone, particularly when a local anesthetic is used, to maintain a continuous segmental sensory block.¹⁶ Epidural infusion of local anesthetic alone may be warranted for postoperative analgesia as it has been shown to minimize opioid consumption and its related side effects; however, this method also has adverse effects.⁵ The use of local anesthetic alone in epidural analgesia is associated with significant failure rates, relatively high incidence of motor block and blockage of sympathetic fibers contributing hypotension.²,¹⁵ Generally, lower concentrations of bupivacaine or ropivacaine are used to avoid these issues due to their differential and preferential clinical sensory blockade with minimal impairment of motor function.¹⁵

Conversely, opioids may be used alone for postoperative epidural infusion yet are also not without their own adverse side effects.¹⁵ Pruritus is one of the most common side effects of epidural administration of opioids.¹⁷ Nausea and vomiting is associated with neuraxial opioids and may be related to the cephalad migration of opioids within the CSF to the area postrema in the medulla. Urinary retention also occurs more frequently with opioid epidural administration than with systemic opioid delivery, which may be attributed to spinal cord opioid receptors decreasing the strength of detrusor muscle contractions.¹⁵

Though respiratory depression has always been an area of major concern regarding opioid use regardless of which route it is administered, neuraxial opioids used in appropriate doses are not associated with higher rates of respiratory depression than systemic administration. Risk factors that do increase respiratory depression with neuraxial opioids include increasing dose, increasing age, concomitant use of systemic opioids or sedatives, possibility of prolonged or extensive surgery, and the presence of comorbid conditions.¹⁸

Myriad adverse effects of epidural analgesia can be attributed to side effects of administering drugs through the neuraxial route. Fortunately, the rates of side effects for PCEA are favorable and comparable to those reported with CEI; their incidence is 1.8%-16.7% for pruritus, 3.8%-14.8% for nausea, 13.2% for sedation, 4.3%-6.8% for hypotension, 0.1%-2% for motor block, and 0.2%-0.3% for respiratory depression.¹⁹ Despite many studies, the optimal local anesthetic and opioid dose for providing the lowest pain scores along with the fewest
medication-related side effects is unknown and further investigation is needed. However, general consensus of many acute pain specialists is toward a combination of low-concentration local anesthetic plus an opioid in an attempt to improve analgesia while minimizing aforementioned side effects, as it can provide analgesia superior to that of either analgesic alone.¹⁵ A lipophilic opioid is commonly used secondary to its rapid analgesic onset and shorter duration of action that is more suitable for use with PCEA.¹⁵ With the onset of analgesia also comes the potential for respiratory depression more quickly seen with lipophilic opioids in PCEA over hydrophilic agents.

Other elements of PCEA have received particular attention over the years. The use of clonidine as an adjuvant medication when used in a local anesthetic-opioid combination PCEA demonstrated a reduction in incidence of opioid rescue without negatively affecting hemodynamics.¹¹ Additionally, consideration should be made as to the location of insertion of the epidural catheter. Epidural catheters inserted at a site congruent with the dermatome level of the incision infuse analgesics to the appropriate region, thus, providing superior analgesia, minimizing drug requirements with their associated side effects and decreasing morbidity.¹⁵ Of note, there is an increased risk associated with placement of an epidural in the thoracic region.

Epidural analgesia has the potential benefits of decreased morbidity, such as fewer cardiopulmonary complications, less thromboembolism, better mental status, earlier restoration of gastrointestinal function, enhanced functional exercise capacity, and earlier discharge from the hospital.¹¹ A large database study further supports the conclusion that mortality is lower for patients who receive perioperative epidural analgesia, especially with a local anestheticbased analgesic solution that attenuates the pathophysiologic response to surgery.¹¹,¹⁵ Metaanalysis of randomized data from 141 trials found that this overall reduction in mortality was by ˜30%, though these results were primarily in orthopedic patients.¹⁵

Use of epidural analgesia can decrease the incidence of a variety of postoperative complications, such as gastrointestinal, pulmonary, and possibly cardiac-related issues.¹⁵ By inhibiting sympathetic outflow, minimizing total opioid consumption, and mitigating spinal reflex inhibition gastrointestinal system, postoperative thoracic epidural analgesia can help propagate return of gastrointestinal motility without compromising bowel vessel anastomosis.¹⁵ Overall, PCEA use is associated with earlier fulfillment of discharge criteria when compared to those who receive opioid epidural analgesia.¹⁵

In patients undergoing abdominal and thoracic surgery, epidural use for postoperative analgesia has shown decreased postoperative pulmonary complications, likely by preserving postoperative pulmonary function via adequate analgesia, therefore, reducing “splinting” behavior and attenuating the spinal reflex inhibition of diaphragmatic function.¹⁵,²⁰ In a recent metaanalysis, thoracic epidural analgesia with a local anesthetic-based regimen also had a lower rate of incidence of pulmonary infections and complications.¹⁵,²¹

Furthermore, postoperative thoracic epidural analgesia may decrease the incidence of postoperative myocardial infarction. This may be due to attenuation of both the stress response and hypercoagulability, superior postoperative analgesia, and favorable redistribution of coronary blood flow. These findings are in alignment with the known physiologic benefits of thoracic epidural analgesia, such as a reduction in the severity of myocardial ischemia or size of infarction and attenuation of sympathetically mediated coronary vasoconstriction.²¹

There may also be an association between the use of neuraxial anesthesia and immune function. It is possible that cancer recurrence and metastasis may be lower in patients who receive paravertebral or epidural analgesia vs receiving conventional systemic opioids after mastectomy or prostatectomy.¹¹ In a recent meta-analysis of 14 studies including a range of cancer types, a positive association between epidural analgesia and overall survival was demonstrated.¹¹ Additionally, epidural analgesia for total hip or knee replacement may decrease the risk of surgical site infections compared with general anesthesia.¹⁵

We have discussed many of the benefits of the use of PCEA thus far; however, it is important to note that PCEA is not suitable or advantageous for every type of surgery or patient.
Hansdottir et al. demonstrated in their randomized control study that with regards to elective cardiac surgery, thoracic PCEA offers no major advantage with respect to hospital length of stay, quality of recovery, or morbidity when compared with IV-PCA.²² In general, the overall potential benefits of PCEA must be weighed against the potential risks associated with placement of a catheter, which include epidural hematoma, infection, or neurological injury.²²

The concurrent use of anticoagulants and neuraxial analgesia has been topic of much debate over the years with the advent of more potent anticoagulants for thromboprophylaxis, further limiting the use of PCEA because of an increased incidence of spinal hematoma.²³ The American Society of Regional Anesthesia and Pain Medicine has a series of guidelines based on the available literature for administration of neuraxial techniques in the presence of various anticoagulants and antiplatelet therapy. Still, the literature is constantly changing and no definitive conclusions have been reached despite numerous investigating studies.²⁴

As for neuraxial associated neurologic injury, one review revealed that the rate of neurologic complications after central neuraxial blockade is <0.04% and after a peripheral nerve block is <3%.¹⁵ Overall, permanent neurologic injury after any type of neuraxial blockade is rare in contemporary anesthetic practice.¹⁵

Though there may be a positive correlation with immunity associated with epidural placement as discussed previously, direct infection from postoperative epidural analgesia placement may result from exogenous or endogenous sources.¹⁵ Central infection such as meningitis and spinal abscess associated with epidural analgesics are rare, <1 in 10 000.²⁵ However, a more frequent incidence has also been observed, 1 in 1000, in patients who had a longer duration of epidural analgesia or coexisting immunocompromising or complicating diseases.¹⁵,²⁵ There may also be a relatively higher rate of superficial inflammation or cellulitis (4%-14%) with longer duration of catheterization.¹⁵ With that said, epidural analgesia in the general surgical population is typically limited to short-term catheter use of <4 days.¹⁵