ASRA Pain Medicine Update

Authors

Benjamin Vaghari,  MD
Assistant Professor of Anesthesiology and Critical Care Medicine
The Johns Hopkins Hospital
Baltimore, MD

Kishor Gandhi, MD, MPH Staff Anesthesiologist
University Medical Center of Princeton
Plainsboro, NJ

Eugene R. Viscusi,  MD
Professor of Anesthesiology Director, Acute Pain Management
Thomas Jefferson University Department of Anesthesiology
Philadelphia, PA

Introduction

Intravenous patient-controlled analgesia (IV PCA) is a widely accepted standard for management of acute postoperative pain.  PCA devices consist of programmable pumps and activation buttons.  The ordering physician controls the infusion rate, bolus volume, maximum allowable hourly dose, and lockout time.  The patient controls the activation button triggering a bolus opioid dose through an intravenous line.    Lockout time serves as a major component of the inherent safety mechanism of PCA to prevent accidental patient overdose.  Patients will be unable to stack bolus doses of opioid with repeated presses of the activation button.  Additionally, if a patient administers too much analgesia, they will experience sedation thus inhibiting further self-administration.^[1] This article will discuss the benefits, drawbacks, typical opioids used, and useful adjuncts in pain management via IV PCA.

Benefits of IV PCA

The major benefits of IV PCA include its efficacy, safety, and patient satisfaction.  The advantage of any PCA modality is that the patient has more control of the timing of analgesia administration when compared to clinician controlled analgesia.  In theory, IV PCA use will decrease the analgesic gaps by reducing the time between patient request and analgesic administration.  A meta-analysis by Ballantyne et al reported a significantly greater analgesic efficacy (5.6 on a pain scale score 0 to 100) when IV PCA was compared with intramuscular (IM) bolus analgesia.^[2] Another meta-analysis also reported a similar improvement with IV PCA as compared to IM analgesia (a difference of 8.0 on a pain scale score 0 to 100).^[3] A review of various analgesic methods reported patients experiencing moderate to severe pain at 24 hours post-op were 67.2% for IM opioid and 35.8% for IV PCA opioid administration.^[4] Another meta-analysis evaluated 32 randomized, controlled trials comparing IV PCA to the more traditional clinician controlled analgesia via IM, IV, or subcutaneous routes.^[5] They found that analgesic efficacy was significantly in favor of IV PCA over more traditional methods though this benefit disappeared when only pain intensity and pain relief were examined.  Another benefit of IV PCA is high patient satisfaction with the modality.^[6-8] Even when overall analgesia is equivalent, patients feel more satisfied when they have access to a PCA modality.  Additionally, evidence supports that IV PCA reduces morbidity and time to hospital discharge when compared to IM analgesia.^[9]

Side Effects associated with IV PCA

Despite the many benefits of IV PCA for post-operative pain relief, the modality does suffer a number of shortcomings.  Adverse events of IV PCA include the common side effects typical of opioids including nausea, vomiting, constipation, pruritus, respiratory depression and sedation.^[10] Overall, a number of meta-analyses have shown similar side effect risks from opioids administered either by traditional methods or IV PCA.^[3],[5] The most serious and most concerning side effect is respiratory depression with resulting hypoxia potentially leading to injury.^[11] A review in 2004 examining the respiratory effects of acute postoperative pain management found the average incidence of respiratory depression with IV PCA ranged from 1.2% to 11.5% using the criteria of hypoventilation and oxygen desaturation respectively.12  For comparison, this review also reported respiratory depression ranges of 0.8% and 37% for IM and 1.1% and 15.1% for epidural analgesia based on the criteria of hypoventilation and oxygen desaturation respectively.^[12] A later study by the same authors on side effects with IM, IV PCA, and epidural analgesia found nearly equivalent incidence of both mild and excessive sedation for IM and IV PCA opioid analgesia.^[13] Risk factors for respiratory depression include but are not limited to use of a background infusion, elderly patients, concurrent administration of sedatives or additional opioids, and pre-existing respiratory compromise.^[11]

Choice of Opioid

A number of different opioids are commonly used in IV PCA devices for post-operative analgesia (Table 1).  Morphine, fentanyl, and hydromorphone are commonly used, and each has a slightly different side effect profile.  Meperidine has largely fallen into disfavor as a choice because of the side effects associated with the toxic metabolite, normeperidine.

Morphine is the most commonly used opioid in IV PCA.  Typical bolus doses range from one to two milligrams.  Morphine is metabolized predominantly by the liver and has active metabolites (morphine-3-glucuronide and morphine-6-glucuronide) that can accumulate in patients with renal failure. 

Hydromorphone is 8:1 times more potent the morphine, has a similar side effect profile, and can also accumulate in renal disease.  As a more lipophilic drug, hydromorphone reaches peak effect in approximately ten minutes because it penetrates the blood-brain barrier more quickly than morphine.  Because it is more potent than morphine, bolus doses are smaller (0.2 to 0.4 milligram). In a double blind study comparing morphine to hydromorphone (at equipotent doses)by Rapp et al, there was little difference in pain relief or side effects.^[14]

Fentanyl is a synthetic opioid that is highly lipid soluble with a time to peak activity of only 6 minutes.  Fentanyl effect tends to dissipate quickly as the drug diffuses away from receptors, but with prolonged infusions the true metabolic half-life of 7 hours may be more evident.   Fentanyl is often used in renal patients since it has no active metabolite.  Overall, there are a number of studies comparing one opioid to another in terms of both efficacy and side effect profile often showing similar pain relief or side effects.^[15-18] However, these studies are conducted in general populations of patients.  Patients with specific characteristics may benefit from specific opioids.

In a three way crossover, double blinded randomized controlled study Woodhouse et al demonstrated that despite equal analgesia of morphine, pethidine, and fentanyl, patients found they were better able to tolerate one opioid over the other.^[19] Given the results of this study, individual patients may benefit from increased flexibility in opioid selection.  Further work is needed with specific patient populations to determine if opioid selection may improve efficacy or tolerability.

Table 1. Typical IV PCA Settings for Opioids

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Opioid Tolerant Patients

In contrast to opioid naive patients, opioid tolerant patients require additional adjustments when using IV PCA as the main source of analgesia.  Opioid tolerant patients have significantly higher opioid requirements compared to opioid naïve patients in the post-operative period.^[20] Additionally, opioid tolerant patients often report higher pain intensity ratings at rest and with movement than opioid naïve patients despite increased sedation.^[20] However, given the variability in opioid requirements in these patients, there is little evidence to guide initial bolus dosing.  Bolus dosing as well as choice of opioid can be adjusted in the postoperative period as needed based on patient response.^[21] Alternatively, the patient’s usual opioid dose can be given orally if possible or converted into a background infusion without adjusting the starting bolus dose.  In a study by Davis et al, they attempted to calculate the required post-operative opioid dose by using a fentanyl challenge in the preoperative period.  This allowed them to determine the dose required for postoperative analgesia which was then converted into a background infusion and bolus dosing.^[22] Overall, appropriate IV PCA adjustments in opioid tolerant patients is often better served by using objective criteria, such as respiratory rate or demand use, rather than subjective criteria.   When managing opioid tolerant patients, it is important to continue baseline oral opioids up to the time of surgery.  Given that most patients may tolerate oral intake shortly after surgery, continuing oral opioids (particularly extended release), simplifies pain management and facilitates later oral conversion.

PCA Adjuncts

While opioids are the mainstay in IV PCA analgesia, other drugs have been added separately or as adjuvants to IV PCA with the hope of improving pain relief and reducing side effects.  Low dose ketamine has been added as either a continuous infusion or directly to the PCA.  Supplemental ketamine infusions in combination with IV PCA opioids has been shown to reduce morphine requirements in the first 24 hours of the postoperative period as well as nausea and vomiting when given as an infusion.^[23] On the contrary, a review of double-blind clinical trials involving ketamine as an adjuvant to opioid PCA infusions found no improvement in analgesia.^[24] Overall, separate continuous ketamine infusions  (as adjunts to PCA) appear to work somewhat better than PCA ketamine either alone or in combination with opioid.

Clonidine given immediately in the post-operative period has been shown to improve pain intensity ratings within the first 12 hours and to significantly reduce nausea and vomiting during the first 24 hours with no difference in overall opioid consumption.^[25]

Another intravenous adjunct, ketorolac, has been shown in a double-blind study to have an opioid sparing effect with no difference in pain scores when combined with morphine for IV PCA compared to IV PCA morphine alone.^[26]

A more recent study examined the role of IV acetaminophen as adjuvant to fentanyl PCA in pediatric patients.^[27]The addition of acetaminophen to IV PCA reduced fentanyl dose, vomiting and sedation by more than 50% in the pediatric population.

At its inception, IV-PCA was considered a “stand-alone” technique.   Current approaches are more likely to be multimodal combining non-opioids such as non-steroidals, COX-2 selective inhibitors, acetaminophen, and most recently gabapentanoids (see article on multimodal analgesia by May Chin, MD). Many postoperative patients will tolerate the addition of oral non-opioids in conjunction with IV-PCA.

PCA Medical Device Events

IV PCA has been demonstrated to be both safe and efficacious.  However, IV PCA analgesia has the potential for medication errors from patient, operator, and the PCA device itself.^[1][28] A recent study examined Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) reports related to IV PCA use for postoperative analgesia during a two year period ending in 2003.  The authors found 2009 IV PCA medical device events with 1590 (79.1%) classified as possible device safety events.  In addition, 106 out of 131 events related to operator error were a result of programming errors.^[29] 

Given the ever present potential for human error, PCA pumps have been improved with software enhancements and bar coding.  Many new pumps contain drug libraries and have typical dosing patterns to reduce the likelihood of keying or programming errors.^[30]A prospective, randomized time-series trial compared the serious medication errors recorded using “smart pumps” with the support software on and off.  The pumps recorded 180 serious medication errors for 744 admissions over an 11 month period with no differences between the software in the “On” and “Off” mode.  The pumps themselves appeared not to reduce the impact of errors due to bypasses of the software.^[31]

In addition to sources of error, IV PCA has other shortcomings.  Hospital staff require training in the proper use of PCA devices.  Also, staff must spend significant time in programming and operating the devices.  The Joint Commission now recommends that two nurses document PCA programming.  While this may reduce errors, it increases the burden on nurses. Presently, only morphine and meperidine are commercially available; all other opioids must be prepared by the pharmacist or obtained from a compounding pharmacy. The entire process of care related to PCA involves many steps and involves many individuals. Hence the true cost of PCA is considerably more than the cost of the drug and tubing.

Patients also must remain connected to the IV line, PCA pump, and pole.  This can potentially restrict movement in the important post-operative period.  An audit of IV PCA use in postoperative surgical period found that 21% of patients reported mobility restrictions related to their PCA use.^[32]

PCA Clinical Pearls

1. Avoid concurrent basal infusions since this increases the risk of respiratory depression without clear benefit. When utilized in opioid tolerant patients, continuous monitoring of oxygenation and respiration is strongly recommended.
2. The most recent guidelines on acute pain management from the American Society of Anesthesiologists support an around-the-clock non-opioid multimodal analgesic platform to reduce the reliance on opioids. PCA with multimodal analgesia achieves this goal in patients requiring parenteral medications.
3. IV-PCA continues to be associated with medication errors and programing errors even with incorporation of Smart Pump technology. Hospital-wide standardization of PCA is mandatory to reduce errors. Availability of only two dose strengths (standard and a single high dose) reduces confusion and resulting medication errors. Standard PCA drug preparations should be equipotent concentrations to minimize the impact of accidental drug swaps. A single, custom high dose equivalent PCA concentration is recommended.

Summary

IV PCA is a safe and effective analgesic technique for managing pain with a track record of more than two decades. IV PCA offers advantages over intermittent bolus opioid techniques.  None the less, IV PCA, like other opioid analgesic approaches, may be limited by familiar opioid related side effects.  In addition, IV PCA is a complicated process involving many steps and individuals which leads to increased opportunity for medication errors and cost. The addition of nonopioid analgesic adjuncts reduces total opioid requirements and opioid related side effects.  Future advances in PCA technology must target the continuing occurrence of medication errors and programming problems.  In addition, less invasive technologies (needle-free delivery) may reduce some of the current PCA limitations.

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