Managing Postembolization Syndrome–Related Pain after Uterine Fibroid Embolization

Uterine fibroids are the most common neoplasm affecting women, occurring in more than 70% of women prior to menopause. Of that 70%, 25% have symptoms severe enough to warrant treatment. ¹ Symptoms range from abnormal uterine bleeding, bulk symptoms with urinary and bowel incontinence, dyspareunia, infertility, and debilitating chronic pain. ²

Since its introduction in 1995, uterine artery embolization (UAE) has evolved into a well-established, safe, and effective minimally invasive, uterine-sparing procedure for the treatment of symptomatic uterine fibroids. ^{3 4 5} Annually, greater than 25,000 UAE procedures are performed worldwide. ⁶ Despite its successes, a persistent challenge and impediment to more widespread use of UAE has been management of postprocedure pain as a result of postembolization syndrome (PES). Inadequate pain control is the most common indication for admission and readmission. ⁷ Predicting the degree of PES is challenging. The range of severity may vary based on intrinsic patient factors, fibroid size and location, imaging characteristics, or preprocedural symptoms. ⁸ New techniques and pain regimens can be applied to manage symptoms and significantly improve patient satisfaction.

The objective of this review is to discuss pain management options after UAE by summarizing the current available literature.

Etiology of Pain Associated with Postembolization Syndrome

PES is experienced by the majority of patients who undergo UAE and is characterized by pelvic pain and cramping, low-grade fever, nausea, vomiting, loss of appetite, leukocytosis, and malaise in the first few days postprocedure. ⁹ PES is thought to be caused by ischemia and tissue necrosis after embolization leading to inflammation. ^{9 10} On a cellular level, ischemia leads to acidosis from increased anaerobic metabolism. This leads to a loss of membrane integrity and release of chemical mediators that stimulate chemosensitive receptors that activate an inflammatory cascade. ¹¹ In the case of UAE, ischemia of the normal myometrium is believed to be the primary source of pain.

Post UAE pain usually worsens during the first 2 to 3 hours after UAE and remains constant for approximately 12 hours, at which time many women describe its persistence at a lower level. ¹¹ However, the intensity of PES varies greatly and, at present, there are no published identifiable factors that can predict pain severity. Baseline fibroid burden cannot be used to predict postprocedural pain and the severity of pain experienced cannot be used to predict outcomes. ⁸

It is important to note that this review focuses on pain control after UAE and not on the additional components of PES which include fever, nausea, and fatigue, which can peak after 2–3 days.

Medications Used for Pain Control

Medications for pain control should be administered pre-, during, and postprocedure. Suggested pain control regimen used by the authors is outlined in Table 1 . The table does not include pain medication used for moderate sedation, which is how UAE is most commonly performed. Ultimately, adequate pain control should allow for UAE to be an outpatient procedure.

Table 1. Suggested pain control regimen .

Preprocedure and intraprocedure
Acetaminophen 1,000 mg PO 30–60 min before UAE or rectally upon conclusion of the procedure
Ketorolac 60 mg IV during embolization
Lidocaine 1% 100 mg IA into each uterine artery after stasis achieved
Superior hypogastric nerve block
• Bupivacaine 0.025% 20 mg
• Kenalog 40 mg
Postprocedure recovery
Hydromorphone 0.5–2.0 mg IV every hour as needed; with transition to oral oxycodone 5 mg PO prior to discharge
Discharge pain medications
Ketorolac 10 mg PO every 6 h × 4 d
Ibuprofen 800 mg PO every 8 h × 14 d to start after ketorolac
Percocet 5/325 or oxycodone 5 mg 1–2 tab PO every 4–6 h as needed a

Abbreviations: IA, intra-arterially; IV, intravenously; PO, by mouth; UAE, uterine artery embolization.

^aWith stool softeners and antiemetics due to known side effects of opiates.

Acetaminophen

Acetaminophen is widely used as an effective and safe analgesic. It is the most commonly prescribed drug for the treatment of postoperative pain in both monotherapy and multimodal regimens. ¹² It is available for oral, rectal, or intravenous (IV) administration. Currently, no consensus exists on the use of acetaminophen for the management of PES after UAE. However, several studies suggest its efficacy in PES as described later.

In their study in 2007, Lampmann et al ³ recommended an aggressive inpatient protocol that focuses on early pain management using rectal administration of acetaminophen. This pain regimen includes IV opiates through a patient-controlled analgesia (PCA) pump started preprocedurally with 1,000 mg acetaminophen suppository placed immediately postprocedure. With early pain control via preprocedure PCA and postprocedure rectal 100 mg diclofenac and 1,000 mg acetaminophen suppositories every 4 hours, they were able to keep the pain under control with decreased use of opiates after UAE. By treating the periprocedural pain aggressively in anticipation of postembolization discomfort, patients were able to be discharged on postoperative day 1.

Using IV acetaminophen and combining it with IV ibuprofen, Chaabane et al ¹³ showed that less opioid medication was used in comparison to the group prescribed IV ketorolac only. The authors suggest a benefit to the combination treatment, as the early data demonstrated a trend toward less opioid usage with better pain control.

Oral and IV acetaminophen were used in the regimen described by Bilhim and Pisco ¹⁴ who performed the vast majority of their UAEs as outpatient procedures with median pain of 2.5/10 in first 8 hours and no readmissions for pain control. This is significantly lower than the mean pain of 5.7 reported by Siskin et al. ¹⁵ Bilhim and Pisco use 1 g acetaminophen IV in addition to 2 g IV metamizole, antiemetics, and anti-inflammatories after embolization. Patients with mild symptoms were transitioned to acetaminophen PO 325 mg and discharged within 4 to 8 hours after their procedure with acetaminophen 325 mg PO, tramadol 37.5 mg PO, and codeine 30 mg PO with acetaminophen 500 mg PO as needed at home.

No current studies have compared the different routes of acetaminophen administration in UAE. Hansen et al ¹⁶ demonstrated that IV acetaminophen posthysterectomy was associated with shorter hospital stays and improved patient outcomes. IV and oral routes of administration offer greater bioavailability of the drug; however, in caesarean sections, rectal administration showed greater quality and duration of postoperative analgesia, suggesting that increased local site concentration of analgesics is more important than systemic drug bioavailability. ¹⁷ Johnson et al ¹⁸ found that PO acetaminophen 60 minutes before cholecystectomy was noninferior to postoperative IV acetaminophen.

Given the variability of acetaminophen administration and dosing in the studies discussed earlier, further investigation is required to optimize administration and use of acetaminophen. However, despite the variability in data, it shows promise when used in a multimodal pain strategy in reducing symptoms of PES after UAE.

In our practice, we use 1 g acetaminophen, either given orally 60 minutes before intervention or immediately after the conclusion of the procedure rectally. It can also be given IV during the procedure; however, it is not routinely used primarily due to its high cost. Additionally, IV acetaminophen at our institution, like many, can only be administered by anesthesiologists or critical care specialists, further limiting its use.

Nonsteroidal Anti-inflammatory Drugs

Inflammation is a central component in the symptom complex of PES. Therefore, the authors believe nonsteroidal anti-inflammatory drugs (NSAIDs) are an essential part of managing postprocedural pain. These are often used in conjunction with opioids, as they work through different pain-inhibitory pathways providing synergistic pain relief without an increase in side effects. ¹⁹

The most common and widely used NSAID is ibuprofen. ⁷ It is readily available without prescription and inexpensive. Hovsepian et al ⁷ compared the effectiveness of rofecoxib with ibuprofen as an anti-inflammatory in the first 5 days after UAE. The authors theorized that the multiple doses needed per day to maintain optimal blood concentrations of ibuprofen and gastrointestinal irritation were a barrier to maintaining medication adherence for successful pain control. Rofecoxib, a selective COX2 inhibitor, would theoretically have fewer side effects and less frequent dosing. However, other studies showed that prolonged use (>18 months) increased risk of cardiovascular disease. ²⁰ Other COX2-specific inhibitors, such as celecoxib, have not yet been studied in the setting of UAE but could potentially be successful options if ibuprofen is not tolerated. In the treatment of arthritis, celecoxib was shown to be noninferior to naproxen and ibuprofen with regard to cardiovascular safety and showed no difference in postprocedural pain or narcotic use. ²¹

Bilhim and Pisco ¹⁴ credited their effective pain control strategy to the preprocedural use of 1,000 mg PO naproxen the night before UAE. Given the half-life of naproxen is 12 to 15 hours, patients are under its anti-inflammatory actions during and after the procedure. Patients are then discharged on scheduled naproxen 500 mg and analgesics acetaminophen and opioids for breakthrough pain control. They hypothesized that continued use of anti-inflammatory drugs like naproxen after discharge is essential for the prevention of pain the first night after UAE. ^{14 22} Discontinuation led to some readmissions due to pain. Although the authors were able to demonstrate an effective regimen for overall pain control, the complex list and timing of different drugs made it hard to achieve successful pain control in all patients. Streamlining protocols with a focus on reducing heavy medication regimens is warranted to provide a more standardized method for post-UAE pain control.

Ketorolac

Another NSAID that is often used in UAE is ketorolac. It has strong analgesic properties and moderate anti-inflammatory activity and when given with other analgesics often provides additive effects. It is a nonselective COX1 and COX2 inhibitor with 100% bioavailability via all routes with hepatic metabolism, renal and biliary excretion, and a half-life of 3 to 9 hours. Administration via coated particles and IV offers fast-acting analgesic and anti-inflammatory effects in both a systemic and localized approach facilitating UAE as an outpatient procedure. ¹⁴

Bilhim and Pisco ¹⁴ relied on IV ketorolac and ketoprofen during the procedure and IV ketorolac and piroxicam after to reduce inflammation and ischemic pain. During the procedure, IV ketorolac was administered twice (total amount: 60 mg) before the embolization of each artery with polyvinyl alcohol particles mixed with ketoprofen 100 mg. Patients received an additional 30 mg of IV ketorolac postprocedure. In contrast, Siskin et al ¹⁵ administered IV ketorolac after embolization. The goal of this timing is not for immediate analgesia but to coincide the peak analgesia with the early postprocedure period when patients typically start experiencing discomfort. Although there are no direct comparisons between IV ketorolac pre- or postembolization of the arteries, because both authors were able to provide adequate pain control, there might be no significant difference.

In our practice, ketorolac (60 mg) is administered IV at the time of embolization. In addition, the patient is discharged with oral ketorolac to take for several days postprocedure before they transition to another NSAID—usually ibuprofen (800 mg PO every 8 hours for 14 days) or naproxen (500 mg daily for 14 days).

Opioids

Some clinicians argue that NSAIDs alone after UAE are insufficient to achieve adequate pain relief, but when given in conjunction with opiates, pain pathways can be targeted through multiple modalities. Use of controlled-release oxycodone in addition to intrathecal and IV morphine showed reduced pain scores during the first 24 hours postprocedure and less morphine consumption through PCA. ²³ Other common opiates used for UAE are hydromorphone, morphine, and fentanyl and/or acetaminophen with either hydrocodone or oxycodone. ^{3 11 13 14 15} Saibudeen et al ²⁴ suggested that although there were mildly better pain scores in patients receiving opioids, NSAIDs, and acetaminophen, these were not statistically significant.

In our practice, patients receive intraprocedural (as part of moderate sedation) and post procedural opiates. If staying overnight, patients are generally provided a PCA pump. They are discharged with oral opioids (Percocet 5/325 OR oxycodone 5 mg 1–2 tablets PO every 4–6 hours as needed) to use in an as-needed basis in addition to their scheduled NSAIDs. It is important to note that common side effects of these medications include constipation and nausea and patients should also receive medications targeting these.

Dexamethasone

Glucocorticoids are a potent anti-inflammatory agent, as they block both the vascular and cellular phase of inflammation. By decreasing the inflammatory mediators after ischemic changes, pain should theoretically be better controlled. Studies have shown that glucocorticoids, particularly dexamethasone, are effective at reducing postoperative inflammation and pain in procedural settings. ^{25 26} Kim et al used 0.2 μg/kg/h dosing 30 minutes prior to UAE and 0.6 μg/kg/h 6 hours postprocedure. ²⁷ In that study, the group that received dexamethasone required 28% less of the fentanyl PCA, had lower pain scores, and needed fewer analgesics than the control group.

Although variable within our practice, unless contraindicated, most patients receive 10 mg IV dexamethasone preprocedurally to help reduce the inflammatory cascade that is thought to contribute to pain in PES.

Muscle Relaxants

Cyclobenzaprine is one of the most commonly used myorelaxant drugs and was introduced as an adjunct for pain control to relieve muscle spasms in patients with musculoskeletal pain. ²⁸ Although its exact mechanism is unknown, the drug does not act directly on the muscle fibers, neural conduction, or neuromuscular transmission, but does act on pain related to muscle hyperactivity. While it has not commonly been used in the context of UAE, it has been used for symptom relief of pelvic floor spasm. ²⁹ Cyclobenzaprine has also been used for effective pain relief in molar surgery and demonstrated it may be useful in the therapeutic prevention of motor dysfunction. Given cyclobenzaprine has been effective in pain control and prevention of motor excitability in surgical procedures involving muscle, it is reasonable to suggest that the use of cyclobenzaprine post-UAE as an adjunct for PES may prove beneficial as PES is a result of ischemic changes in the uterine myometrium. However, more data are needed to support this statement.

Superior Hypogastric Nerve Block

As described earlier, the pain after UAE follows a consistent pattern. It increases during the first 2 hours postprocedure, plateaus for 8 to 12 hours, and then decreases slowly. ¹¹ Therefore, a pain control strategy that has its maximum effect in the first 24 hours could be an effective pain control method. One such strategy is the superior hypogastric nerve block (SHNB).

The SHNB procedure is outlined by Rasuli et al. ³⁰ Under fluoroscopy, bupivacaine is injected into the hypogastric nerve ganglia at the beginning or conclusion of UAE. The addition of SHNB along with systemic analgesics provides multimodal pain control: painful stimuli production is blocked at the level of the uterus through inhibition of prostaglandins, transmission of painful signals is blocked with SHNB, and opioids inhibit pain recognition at the level of the brain.

Patients who receive a SHNB have reported less traumatic experiences and lower doses of narcotic use compared with patients who do not. ¹¹ Studies have also shown a significant reduction in postprocedural morphine use and mean opioid requirements with shorter hospital stays. ^{31 32} Moreover, some studies have shown that the addition of steroids (40 mg of triamcinolone to 20 mL of 0.5% bupivacaine block) can prolong the duration of SHNB analgesia from 8 to 12 hours to an average of 33.8 hours post-UAE. ³³ In our anecdotal experience, patients who undergo SHNBs are able to be discharged home the same day endorsing appropriate pain control.

The technique entails some risks and can be technically challenging in large patients or those with substantial uterine tumor burden. ³⁰ Fibroids that reach the umbilicus might be a relative contraindication, as it complicates the route of the needle to the nerve plexus. A potential complication is IV injection of bupivacaine which can result in cardiac arrest and convulsion. If toxicity does occur, infusion of lipid emulsion and standard resuscitation measures need to be implemented. The lipid emulsion is thought to work by binding the lipophilic local anesthetic and preventing its binding to cardiac or neural receptors. ³⁴

However, the risk of this in SHNB is thought to be no more severe than the risk with epidural anesthesia because of the use of fluoroscopic guidance to confirm needle location. Visualization of the spatial relationship between the iliocaval junction, aortic bifurcation, and the midinferior L5 vertebral body can be evaluated by magnetic resonance images before the procedure to reduce the risk of IV injection of anesthetic. ³⁴ Several procedural steps are also taken to ensure appropriate site for injection.

The authors consider SHNB an important step toward performing UAE on an outpatient basis, as it provides a safe and effective intervention that significantly reduces pain and analgesic requirements.

Intra-arterial Lidocaine

In their study evaluating the use of intra-arterial lidocaine for pain reduction after UFE, Noel-Lamy et al conclude that the use of preservative-free intra-arterial lidocaine injected directly into the uterine arteries immediately postembolization reduced pain scores during the first 4 hours postprocedure and decreased opiate use. ³⁵ In addition, Duvnjak and Andersen described decreased postprocedural pain in the first 2 hours postprocedure as well as decreased opioid use in the first 24 hours post-UAE. The thought is that lidocaine results in temporary loss of sensation in the remaining patent myometrial branches that are intentionally preserved. ³⁶ However, there was no significant reduction in pain levels in 7 to 24 hours following UFE in either study, likely due to the short half-life of lidocaine.

Katsumori et al ³⁷ did not find a statistical difference in pain levels between patients who received intra-arterial lidocaine and those who did not. However, as Caridi noted, the lidocaine dosage in this study was lower than the two aforementioned ones (80 vs. 200 mg) which may account for the results. ³⁸ Keyoung et al ³⁹ administered lidocaine preembolization leading to vasospasm and early termination in 18 patients. Therefore, administration of embolic particles mixed with lidocaine can reduce complete fibroid infarction due to vasospasm, ²⁴ even when diluted to 0.5%.

The authors suggest intra-arterial lidocaine use for early postprocedural pain control once embolization is complete. Once stasis is achieved in the uterine artery, preservative-free intra-arterial lidocaine (100 mg) is slowly injected into the catheter followed by a saline flush.

Access-Site Selection

The use of transradial access (TRA) has increased in recent years and is associated with improved patient comfort, fewer access-site complications, and earlier ambulation. ⁴⁰ In contrast to conventional transfemoral access (TFA), TRA was reported to have a lower incidence of major vascular complications in UAE, without differences in radiation exposure, fluoroscopy time, or total procedure time. ⁴¹ Liu et al ⁴² reported significantly lower pain scores with TRA access immediately after procedure; however, there was no significant difference found on average pain score after being discharged home. There was also no difference in access-site complications and prior studies reported that TRA was more likely to fail for shorter patients attributable to their smaller radial artery diameter. ⁴¹ Nakhaei et al ⁴¹ concluded that TFA and TRA were comparable in terms of technical and clinical outcomes. One main potential benefit of TRA is the shorter time to ambulation, as early ambulation after procedure has showed decrease incidence of pain, nausea, and vomiting in other embolization procedures. ⁴³ Another potential benefit is the ability to change positions which requires leg bending and is often helpful with uterine cramps.

Conclusion

There is enormous heterogeneity in the treatment of pain related to PES after UAE and there is no clear comparative study demonstrating superiority of any particular pain protocol. However, there are similarities across multiple studies. For example, all studies utilized a multimodal regimen through the use of NSAIDs, acetaminophen, and narcotics. Early, preprocedural administration of anti-inflammatory medication and analgesics showed success in reducing immediate postprocedural pain. The addition of other interventions such as the SHNB and intra-arterial lidocaine shows promising results. Randomized clinical trials comparing the methods with standardized pain scores will help develop an optimal regimen for pain control post-UAE.