Learning Objectives:After participating in this continuing education activity, the provider should be better able to:

1. Identify perioperative replacement medications used to treat opioid use disorder.

2. Differentiate postoperative pain control regimens for patients with opioid use disorder who are undergoing gynecologic surgery.

3. Compose multimodal techniques that incorporate nonopioid and local anesthetic options for management of postoperative pain.

In the United States, more than 600,000 hysterectomies are performed each year.1 Perioperative pain management of major abdominal surgical cases has become a growing interest, as anesthesiologists and surgeons alike work to optimize patient pain control, satisfaction, and clinical recovery. Despite guidelines for multimodal analgesia, patients still report poor pain control postoperatively, which can be linked to patient satisfaction.2 Here, we review the variety of analgesic techniques used in perioperative pain management and address caring for a unique population-patients with known opioid use disorder (OUD). We focus on summarizing differing approaches to postoperative pain control and review the evidence in favor of such therapies, and highlight innovative analgesic techniques. For each clinical situation, the clinician should consider the surgical approach, length of surgery, and patient characteristics to decide which perioperative analgesic regimen is ideal for improved patient recovery. Health care providers need to be equipped to provide perioperative care to patients with OUD. We must institute multimodal methods of pain control to minimize additional opioid exposure for these patients while allowing them to recover comfortably.

Opioid Use Disorder

In 2016, 11.8 million people in the United States misused opioids in the past year and 2.3 million people older than 12 years were living with OUD.3 Opioid abuse is a national crisis, and how to provide care during the perioperative period to patients misusing opioids or in treatment for OUD is a growing concern.

OUD is defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) as "a problematic pattern of opioid use leading to clinically significant impairment or distress" in a 1-year period, accompanied by at least 2 manifestations, as outlined in Table 1.1,4 Of note, this opioid use is not for medical reasons or is in excess of prescribed doses for a medical reason. Patients could be using pharmaceutical opioids or illicit drugs such as heroin for pain relief, central nervous system depression, or euphoria. OUD is an umbrella term that encompasses the former diagnoses of opioid dependence and opioid abuse disorder. Opioid tolerance is defined as needing more and more medications to receive the same effect or gaining less effect from the same amount of opioids.1

Table 1. Diagnosis of Opioid Use Disorder

Treatment of OUD often involves a variety of replacement medications (Table 2), administered after a medically supervised withdrawal period, with the goal of patient abstinence from pharmaceutical or illicit opioids. Figure 1 illustrates a perioperative management pathway. The goal of therapy is to titrate the replacement medication to a level that suppresses withdrawal symptoms or allows them to be tolerable. Medication is introduced (ie, induction) at a starting dose and titrated using a measurable scale of withdrawal symptoms (Clinical Opiate Withdrawal Scale). Opioid agonists represent one class of medications used; they decrease cravings and withdrawal symptoms by binding to the [micro]-opioid receptors. Methadone is a long-acting full opioid agonist that is a Schedule 2 controlled substance. It is usually dosed daily in a controlled setting, like a methadone maintenance program where patients attend the clinic daily. Doses correlate with the level of methadone needed to prevent withdrawal symptoms, with an initial dose of 20 mg that is then titrated by 5 to 10 mg every few days. The usual maintenance dose is between 60 and 120 mg/d. Adverse effects include constipation, drowsiness, sweating, prolonged QTc interval, and hyperalgesia. As it is a full agonist, it is possible to overdose on methadone.

Figure 1. Perioperative management of pain in patients with opioid use disorder.

Table 2. Opioid Abuse Disorder Maintenance Agents

Buprenorphine is a partial [micro]-opioid agonist that has a higher affinity for the [micro]-opioid receptor than heroin or other pharmaceutical opioids. Thus, it can lead to opioid withdrawal. Buprenorphine is commonly combined with naloxone (Suboxone) in a sublingual tablet to prevent individuals from crushing up the tablets and injecting them IV. Naloxone, an opioid antagonist, would cause immediate withdrawal if given IV, but it is not active sublingually. As Schedule 3 drugs, both buprenorphine and buprenorphine-naloxone can be prescribed in clinics with practitioners trained in the use of these medications and the management of OUD. After an induction period, patients can take their dosing at home. Buprenorphine is available in a monthly extended-release injection, while buprenorphine-naloxone is available as a daily sublingual tablet. Side effects of buprenorphine include sedation, constipation, and nausea. Patients identified with OUD that need to be started on buprenorphine are typically induced when they start to exhibit withdrawal symptoms at doses of 2 to 4 mg/d. Doses are increased by 2 to 8 mg/d until they no longer exhibit withdrawal symptoms. The average dose after induction with buprenorphine-naloxone (Suboxone) is 8 to 16 mg/d.5

Naltrexone is an opioid antagonist that works to block the effects of opioids and is used as a relapse deterrent. Patients who are actively using opioids can go into sudden withdrawal if given naltrexone; therefore, it should be used in those who have already gone through medically supervised withdrawal. Other side effects include fatigue, dizziness, nausea, and headache. In addition, opioid antagonists rapidly decrease a patient's tolerance to opioids and can increase the risk of death if the previously used dose of opioids is taken. Naltrexone is available in oral form with an average maintenance dose of 50 mg/d after an initial dose of 25 mg/d. There is also an intramuscular depot form of 380 mg given every 4 weeks.

The use of treatment medications for OUD is variable in the perioperative setting. The American Society of Addiction Medicine provides recommendations for the treatment of patients with OUD during the perioperative period. In their 2020 report, they address methods to continue opioid maintenance treatment and employ short-acting opioids for acute postoperative pain. The use of adjuvant nonopioid medications is encouraged, while allowing short-acting medication when necessary.5

The perioperative plan for OUD replacement medication use varies based on which agent the patient is taking. Patients undergoing surgery who take methadone should take their normal dose of methadone the day of surgery. Patients who are hospitalized should still receive their normal daily dose of methadone, and if clinic confirmation of dosing is not available, then patients should be started on a dose of 30 mg/d to prevent withdrawal. As methadone is a full agonist, patients may be tolerant and need higher doses of short-acting opioids to address acute pain in the postoperative period. Buprenorphine can also be continued through the perioperative period. For both methadone and buprenorphine, the dose and frequency can be increased (split dosing) to manage acute pain.

Some providers may choose to discontinue methadone or buprenorphine preoperatively, typically 24 to 36 hours before surgery, to increase [micro]-opioid targets and allow for a better response to short-acting opioids. If this strategy is employed, once IV opioid medication is no longer needed, resumption of OUD treatment medication and dose is recommended as long as they were only withheld for less than 3 days or else induction and titration will need to occur. Typically, methadone or buprenorphine is not discontinued perioperatively, as higher-potency IV forms of full agonist opioids will be effective for pain control.5

As for naltrexone, the American Society of Addiction Medicine recommends discontinuing use 72 hours before surgery for the oral dose and 30 days before surgery for the depot form.5 Usual postoperative pain control strategies should be employed and naltrexone can be restarted once patients are off short-acting opioids for 3 to 7 days. Restarting this medication should occur under the supervision of a pain management specialist given the severity of withdrawal symptoms that can be precipitated with naltrexone.

Patients with OUD or on opioid replacement therapy generally need their baseline dose of opioids covered and then up to 2 times the normal amount of short-acting opioids to control pain and prevent withdrawal.6 In balancing pain control and respiratory depression from opioids, many patients will reach the maximum tolerated dose but still have acute pain control needs. Thus, multimodal analgesia using nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, regional analgesia, and alternative analgesic medications is important when treating patients with OUD.

Opioid Analgesics

Oral and IV Opioids

Opioid medications are the most commonly used agents for postoperative pain control. Opioids can be dosed and titrated in different forms and route of administration. Table 3 includes short-acting opioid analgesics employed for postoperative pain control, highlighting agent characteristics. Consider lower dosage for opioid-naive and higher for opioid-tolerant patients.

Table 3. Short-Acting Opioid Analgesics for Postoperative Pain Control

Opioid medications relieve pain by targeting opioid receptors in the brain and blocking the sensation of pain through inhibition of ascending pain pathways. Morphine and codeine are naturally occurring agents whereas the rest are synthetic (hydromorphone, fentanyl, and oxycodone). Benefits of opioid medications include varied dose, ability to titrate, and variety of medication type. Opioids have inherent undesirable side effects due to the generalized central nervous system depression, such as somnolence, decreased respiratory drive, nausea, vomiting, urinary retention, sedation, bowel dysfunction, and a fairly common intolerance profile including pruritus and dermatitis. Due to these side effects, current enhanced recovery protocols include multimodal anesthesia techniques to reduce opioid consumption in the postoperative phase. Regardless, opioids do offer immediate and temporary options for pain control in the postoperative period, yet the growing concern over opioid dependence and abuse should be emphasized when considering postoperative pain control options.

Patients on opioid maintenance medication often require additional short-acting opioid to treat acute postoperative pain. Given the long-acting agonist and partial agonist effects of methadone and buprenorphine, respectively, higher-potency opioids (eg, fentanyl or sufentanil) are suggested to effectively impact [micro]-opioid receptors. These should only be given under the supervision of an anesthesiologist and with adequate monitoring. Patients on buprenorphine are more likely to require additional medication. These patients may benefit from additional doses of buprenorphine or increasing the frequency of the medication to assist with acute pain control.5

Patient-Controlled Analgesia

Patient-controlled analgesia (PCA) allows IV delivery of opioid medication facilitated by patient demand. This allows the patient to administer medication as needed for pain control within prescribed boundaries on the amount of medication delivered. Benefits of the PCA include patient's ability to control dose in a monitored setting, safeguards to prevent overdosing, and ability to use in patients who are not drinking/eating (ie, nothing by mouth). Typically, PCAs are used acutely in the postoperative period until resumption of oral medications can begin. PCAs hold the same risks and side effects as oral opioid medications. Table 4 highlights the 3 main agents used in PCA pumps postoperatively and provides suggested dosages.

Table 4. Patient-Controlled Analgesia-Suggested Opioid Dosage

PCA with a basal rate has been shown to increase the risk of respiratory depression.7 However, in the opioid-tolerant population, basal rates may be needed to fully control pain. With tolerance comes the ability to utilize a basal dose with less risk of respiratory depression. However, care should be used in the elderly, morbidly obese, or patients with obstructive sleep apnea.

Nonopioid Agents

Nonopioid agents are used in combination with opioids postoperatively to provide maximal pain control while limiting undesirable side effects of opioids. Table 5 highlights the variety of nonopioid agents used and recommended dosages.

Table 5. Nonopioid Analgesics

Acetaminophen (Paracetamol)/APAP

Acetaminophen, also known as paracetamol/N-acetyl-p-aminophenol (APAP), has 2 mechanisms of action. It is thought to decrease prostaglandin production through weak inhibition of cyclooxygenase-1 and -2. Although the mechanism is not fully understood, it is also thought to act on the central nervous system through activation of descending serotonin-inhibitory receptors and potential nociceptive systems involved in pain control. It also generates antipyretic effects through inhibition of the heat-regulating center in the hypothalamus. Acetaminophen added to morphine in cases of abdominal hysterectomy for benign pathology resulted in a mean decrease in 24-hour morphine consumption of 8.3 mg.8 A meta-analysis, which included 17 gynecologic randomized clinical trials (RCTs), reported an 8.68-mg decrease in morphine use in the first 24 hours postoperatively when paracetamol was used.9 Furthermore, an RCT in Finland reported reduction in 24-hour oxycodone usage with IV acetaminophen administered at anesthesia induction and every 6 hours for the first 24 hours.10 Providers should be aware of postoperative antipyretic properties and dose limitations, especially in those with liver dysfunction. Some experts recommend lower total limit to 3000 mg for those under 50 kg, with liver dysfunction, known heavy alcohol use, elderly, or dehydrated. In these situations, the dose may be furthered lowered to 2000 mg or withheld.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs work by inhibiting cyclooxygenases-1 and -2 (COX-1 and COX-2), thereby decreasing the production of downstream prostaglandins and cytokines that cause inflammation and pain. NSAIDs are recommended for concomitant use with opioids postoperatively, where up to 30% to 50% opioid sparing has been reported.11 There is a need to be selective when prescribing NSAIDs, as they are associated with a number of adverse effects, including acute kidney injury, which may lead to renal failure and oliguria, platelet inhibition and postoperative bleeding, and gastrointestinal toxicity causing gastric stress ulcers and bleeding. NSAIDs should be avoided in patients with a history of gastric stress ulcers or bleeding or compromised renal function. The elderly should receive lower doses. An additional advantage of NSAID use is the preventive release of inflammatory cytokines in the postoperative period.

A systemic review of 52 RCTs, with 16 of these including data from gynecologic surgical procedures, demonstrated that NSAIDs used with a morphine PCA decreased 24-hour morphine consumption by 15% to 55%, improved visual pain scores, and resulted in a reduced incidence of nausea and vomiting and sedation.12 The meta-analysis mentioned previously also demonstrated NSAIDs to decrease morphine used by 9.45 mg/d with improved nausea and sedation scores.9 Ketorolac offers a high-dose IV formulation of NSAID. In a double-blind RCT, ketorolac administered 30 mg every 6 hours in the first 48 hours after undergoing abdominal hysterectomy resulted in an opioid-sparing effect with decreased need for antiemetic therapy.13 Ketorolac should only be used for a maximum of 5 days.

Local Anesthetics

Local Injections

Local wound injection of anesthetics avoids many of the side effects of other methods used to achieve postoperative pain control, including decreased bowel function and nausea or vomiting associated with opioids or urinary retention and decreased mobility with epidurals. Although theoretically advantageous for analgesic control, little evidence exists for the efficacy of local wound anesthesia. A few smaller trials examining bupivacaine or ropivacaine injection for operative gynecologic laparoscopy cases reported improved pain scores with incision injection,14,15 yet other similar trials with a larger population reported no change in postoperative pain.16,17 An RCT examining the effect of local anesthesia at port sites for laparoscopic gynecologic surgery (eg, salpingectomy, myomectomy, and hysterectomy) demonstrated a decrease in analgesic consumption and pain scores only in the small subset of patients undergoing hysterectomy.18 However no trials demonstrate advantage in laparotomy incisions with traditional local anesthetic, a retrospective study in 200 patients undergoing cytoreductive surgery with laparotomy demonstrated that incisional liposomal bupivacaine decreased postoperative opioid and PCA use.19 The main limitation of incisional injection of lidocaine and bupivacaine is their short duration of action. However, the liposomal formulations can extend the effect to 72 to 96 hours.

Multiple trials have examined the use of local analgesic via paracervical block at time of vaginal hysterectomy. Three randomized controlled trials included the use of bupivacaine or ropivacaine at the time of vaginal hysterectomy. All 3 reported a lower total morphine equivalent use in the first 24 hours and lower pain scores in the first 3 to 8 hours postoperatively.20-22 Two of the trials injected 20 mL of 0.5% bupivacaine with epinephrine and the third injected 50 mL of 0.5% ropivacaine.

Regional Anesthesia

Although narcotic medication is effective in controlling postoperative pain, undesirable side effects such as pruritus, nausea, emesis, and slowing of bowel function make these less than ideal agents. Regional anesthetic techniques have been employed to minimize side effects and decrease the amount of narcotic agent use, with the hopes of improved postoperative recovery.

Epidural Analgesics

Epidural analgesics provide analgesic effect without the side effects associated with systemic analgesics. Anesthesiologists provide an epidural either preoperatively or postoperatively and can leave the epidural catheter in place postoperatively for continued analgesia. Epidural anesthesia works by placement of a catheter into the epidural space followed by bolus and continuous infusions of local anesthetic agent to spinal nerves originating from the spinal cord. In the case of abdominal hysterectomy, placement at the L2-L3 space confers analgesia in the pelvic and lower abdominal dermatomes. This placement may cover pfannenstiel incision pain; however higher, midline vertical incisions may require a thoracic epidural to reach higher abdominal dermatomes. Sodium channel blocker local anesthetic is the agent of choice for providing neuraxial analgesia to spinal nerves; adjuvant epidural opioids are often added (Table 6). Multiple studies of epidural anesthesia/analgesia report improved pain scores, decreased opioid use and opioid-sparing effects.23,24 Barriers to epidural use include limited ambulation and other sequelae related to epidural placement, the risk of epidural-associated hypotension and respiratory compromise, urinary retention, longer anesthesia time, and higher cost.

Table 6. Commonly Used Agents for Epidural Anesthesia/Analgesia

Transversus Abdominis Plane Blocks

Transversus abdominis plane (TAP) block is a local regional nerve block in which local analgesic agent is injected into the neurovascular plane between the transversus abdominis and the internal oblique muscles, providing analgesia in the dermatomal areas from T8 to L1. This area targets the intercostal nerves extending from T7 to T11, the subcostal nerve, and the L1 spinal nerve that divides into the ilioinguinal and iliohypogastric nerves. This provides analgesic relief to sensory nerves innervating the abdominal wall, including the peritoneum and peripheral sensory skin regions, gluteal regions, groin, and upper hip and thigh regions. For a hysterectomy, bilateral injections are made for full abdominal coverage. The analgesic agents used are the same as those used for epidural anesthesia (Table 6); however, only local anesthetics with or without dexamethasone typically are used. Opioids are not typically used with TAP blocks.

The TAP block typically is performed under ultrasound guidance, usually with general anesthesia administered either before incision or at the end of the procedure. The block can either be given as a 1-time dose or continuously via a catheter in the perioperative period. The TAP block is beneficial as it can provide pain control in the area of surgery without the risks associated with neuraxial anesthesia.

The evidence of effectiveness of the TAP block is varied based on the surgical approach. In cases of laparoscopic hysterectomies for benign and malignant disease, multiple randomized controlled trials using a TAP block with bupivacaine or ropivacaine demonstrated no additional analgesic benefits.25-28 In a trial of patients undergoing hysterectomy for a gynecologic cancer via a midline laparotomy, bilateral ultrasound-guided TAP block at incision closure demonstrated no difference in morphine use postoperatively or patient satisfaction.29 A more recent RCT compared 3 types of continuous abdominal wall blocks (TAP vs posterior rectus sheath vs subcutaneous catheters) used in midline laparotomy gynecologic oncology surgery and demonstrated no difference between the techniques in analgesic and antiemetic usage, visual analog pain scores, nausea, emesis, and patient satisfaction.30

Despite mixed evidence, the TAP block does appear to be effective for laparotomy cases via midline incisions with limited evidence for its effectiveness in low transverse incisions, or laparoscopic procedures. These procedures are known to produce less pain and therefore it is logical that additional anesthetic by regional blockage may not be necessary.

Adjuvant Analgesic Agents

Gabapentin

Gabapentin is an antiepileptic used first-line for neuropathy and nerve pain but has been commonly introduced into postoperative pain regimens, especially in cancer cases. Gabapentin and pregabalin are antihyperanalgesics structurally related to the neurotransmitter [gamma]-aminobutyric acid (GABA). They bind to the [alpha]-[delta]-subunit of voltage-gated calcium channels to reduce the release of excitatory neurotransmitters. Although the side effect profile is favorable compared with opioids, the most common side effects include dizziness, somnolence, fatigue, and ataxia. Perioperative use usually involves a preoperative loading dose (eg, 300-1200 mg once) and postoperative dosing of gabapentin (eg, 100 mg every 8 hours, 400 mg every 6 hours, or 1200 mg daily) or pregabalin (eg, 50-150 mg daily split in 2 to 3 divided doses). In a meta-analysis that included 14 RCTs examining abdominal hysterectomies, preoperative gabapentin was found to significantly decrease postoperative opioid use, pain scores, nausea, and vomiting.31 One additional benefit found in an RCT done in abdominal hysterectomy patients was that postoperative gabapentin prevented chronic pain in the first 6-month period.32 The evidence for laparoscopic cases is not as strong. One trial reports that 600 mg of gabapentin before procedure did not decrease pain scores or 24-hour opioid use, but was associated with dizziness.33 Another looking at pregabalin found that typical doses of the medication (150-300 mg) did not decrease opioid consumption, and although the highest dose of 600 mg did reduce opioid consumption, it was associated with unfavorable side effects such as dizziness, blurry vision, and headache.34

Dexamethasone

IV dexamethasone given at the beginning of anesthesia has been found to reduce opioid use, in addition to its known antiemetic effects. A randomized controlled trial in Finland gave 5 to 15 mg of IV dexamethasone at the beginning of a laparoscopic hysterectomy and reported decreased 24-hour opioid consumption.35 This result was also found in a similar RCT, which provided 8 mg of dexamethasone 2 hours before anesthesia in laparoscopic cases.36 In open abdominal hysterectomy cases, although dexamethasone can decrease postoperative nausea and vomiting, it has not shown an appreciable effect on opioid use or pain control.37

Conclusion

The breadth of analgesic options invites personal patient management by both the anesthesiologist and the surgeon. In patients with OUD it is important to plan to incorporate baseline opioid maintenance medication and employ multimodal analgesia to provide effective pain management, decrease undesirable side effects, and curb addiction. When employing multimodal analgesia, surgical approach (vaginal, laparoscopic, or abdominal) can help guide analgesic choices. Special consideration should be given to gynecologic oncology patients who are undergoing more extensive procedures and who may benefit from regional blocks.

REFERENCES