Acute Postsurgical Pain Management in Patients with Cancer

Introduction

Postoperative pain management is an integral component of the perioperative management of patients requiring surgery. Perioperative management starts early, even before the patient is admitted to the hospital for surgical procedures. The perioperative care team’s preoperative optimization of underlying comorbid diseases and associated medications ensures that optimal anesthesia and analgesic strategies are utilized. For example, patients with cardiac disease may have anticoagulants prescribed that need careful discontinuation when neuraxial analgesic modalities, such as epidural catheter placement, are considered. Patients with brain metastases may have compromised neurologic function, which requires careful consideration of centrally acting analgesics. Similarly, patients with hepatic metastases may have impaired metabolic and synthetic liver function and therefore altered drug metabolism and coagulopathy, which may impact the choice of anesthetic and analgesic techniques.

Cancer is one of the leading causes of morbidity and mortality and is associated with a significant burden of pain. The World Health Organization (WHO) executive summary (2018) reported 18.1 million new cases and 9.6 million deaths related to cancer in 2018, with 70% of patients experiencing cancer-related pain while undergoing cancer-related treatment or during the terminal stages of illness. ^, A multidisciplinary approach to pain management in cancer patients is essential and should include pharmacologic, interventional, surgical, and psychologic approaches. Given that surgery remains a cornerstone of cancer care, an acute postoperative pain management strategy is essential. Perioperative pain management in patients with cancer poses distinct challenges that require a systematic, well-thought-out approach starting in the preoperative phase tailored to the individual patient’s surgery, underlying comorbid disease, patient’s previous experience, and outcomes.

Postoperative Pain Management in Cancer Patients

The perioperative team managing patients undergoing cancer-related surgery may experience specific challenges with regard to postoperative pain management. Some of these challenges include the following.

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Abnormal coagulation profile, particularly in patients with liver dysfunction. Impaired liver function and coagulation factors may be related to primary liver cancer, metastatic liver disease, chemotherapy, immunotherapy, or comorbid disease such as hepatitis C. Thrombocytopenia related to cancer treatment or bone marrow infiltration is another challenge that should be considered when considering neuraxial and regional blocks, for example, epidurals, spinal, plexus blocks, and so on. If a preintervention platelet transfusion is indicated, the risk-benefit profile of the planned intervention should be considered. Consideration should be given to preprocedural laboratory investigations, such as partial thromboplastin time (PTT), prothrombin time/international normalized ratio (PT/INR), and platelet count, to avoid hemorrhagic complications and other specialists (e.g., hematologists) consulted for complex clinical cases.
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Immune compromise, for example, neutropenia, may be seen in patients receiving chemotherapy, mandating regular blood counts to monitor their underlying immune state, and for early signs of infection.
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Preoperative analgesia requirements may be associated with opioid tolerance, a recognized side effect of opioid therapy that leads to dose escalation and higher opioid usage. A typical strategy would be to continue baseline long-acting opioids and add short-acting (prn, as required) opioid medications postoperatively.
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Other preoperative conditions that may affect postoperative analgesia requirements and the effectiveness of interventions include neuropathic pain from radiation therapy, metastatic lesions in the spine or around the neural plexuses, inability to maintain steady posture, cognitive deficits due to cerebral metastasis, impaired drug metabolism, and clearance, such as metastatic liver disease and impaired renal function compromised by renal or pelvic cancers.

Various Analgesic Modalities

Successful postoperative pain management involves the application of multimodal analgesic modalities adapted to the surgical procedure and patient needs. Depending on the modality to be applied, specific precautions must be considered. Opioids are the most commonly used pharmacological agents for acute and chronic cancer-related pain. The WHO guidelines for the pharmacologic management of cancer pain in adults and adolescents are among the most commonly used and validated tools in clinical practice. Despite the availability of several rapid and short-acting opioid and nonopioid agents, a substantial number of patients reportedly have undertreated pain, which adversely affects their mood, activities of daily living (ADLs), and level of satisfaction. Some of the most common modalities for postoperative analgesia include the following.

Oral Analgesics

Oral analgesics play a limited role in postoperative analgesia after cancer surgery. Unless the surgical procedure is minor, most cancer-related surgeries require parenteral analgesics. Patients with cancer may receive preoperative oral analgesics (usually opioids) for chronic pain management. These medications should be considered as the patient’s baseline analgesic requirement and then supplemented with other analgesic strategies as necessary.

Preoperative cessation of oral intake may necessitate conversion to parenteral analgesics during the perioperative phase, and the parenteral route continues until the patient can resume oral intake. Newer agents such as sufentanil sublingual tablet system (SSTS) are gaining attention as an option, notably for acute postoperative pain management. A meta-analysis reported that SSTS is a valuable option for managing moderate to severe postoperative pain control, with improved effectiveness and faster onset.

Nonsteroidal antiinflammatory analgesics (NSAIDs) play an essential role in managing patients with bone metastases but should be weighed against the risk of bleeding in patients with gastrointestinal or hepatic disease.

Parenteral Analgesia

A historical article by Roe (1963) on the intravenous administration of morphine for postoperative pain control in adults and children reported that the IV route was significantly more effective than the conventional oral regimen, with a dose reduction from 50–100 mg to 4 mg. Patient-controlled analgesia (PCA) with parenteral opioids is now one of the mainstays of postoperative analgesia after cancer surgery. Intravenous PCA can provide a baseline dosage (which may be equal to or greater than the preoperative opioid dosage), depending on the patient’s needs and the demand dosage at a specified interval. A patient with intact cognitive function may properly administer programmed dosage on an as-needed basis.

Sechzer, the true pioneer of PCA, initially administered small IV doses given on patient demand but administered by a nurse, followed by the development of a pump-driven PCA in 1971. PCA infusion pumps have since evolved in terms of technology, delivery system, flexibility offered to patients, safety features, and portability. A mechanical/electronic device providing PCA is considered superior to IV bolus analgesia. Common opioids used for PCA include morphine and fentanyl, while other agents occasionally administered via PCA infusion pumps include hydromorphone, sufentanil, and rarely meperidine (if the patient is intolerant to other agents). Most modern PCA infusion pumps can be programmed in PCA mode or PCA plus continuous background infusion mode. There are three settings commonly considered when starting a patient on a PCA device: demand dose, background infusion, and lock-out intervals. The lock-out interval is programmed to avoid toxicity, and the demand dose should be closely monitored to avoid side effects.

Continuous infusion along with a patient-administered bolus may be required in patients with cancer undergoing surgical procedures that are on preoperative oral or transdermal forms of opioids. For these patients, the background analgesic requirement should be continued based on the preoperative opioid dosage of the patient.

Parent-controlled analgesia can be used for pediatric patients. This setup requires parents to understand the PCA mechanism and the potential of overdosing the patient by overly enthusiastic or concerned parents. A background dose may be programmed along with a demand bolus dose in patients with high preoperative opioid requirements. It is essential to monitor patients during parent-administered PCA and PCA programs that use a background dosage to prevent respiratory depression.

Nurse-administered intravenous analgesia is commonly observed in the immediate postoperative period in patients who have undergone routine surgery. Once the patient has recovered adequately and requires moderate amounts of opioids, transitioning to a PCA infusion pump is suitable for patients nursed on surgical wards. The nurse-administered route may continue to be required if a patient cannot operate the PCA equipment, for example, due to limitations such as cognitive impairment.

Neuraxial Modalities

Epidural Analgesia

Epidural analgesia is commonly used for postoperative analgesia following major cancer surgery. A well-placed functioning epidural infusion can provide near-complete analgesia without the sedating side effects of oral or intravenously administered analgesics. Epidural catheters are usually placed preoperatively before induction of anesthesia, as the placement of an epidural in the postoperative recovery phase is difficult in patients who are heavily sedated or in pain and thus not very cooperative. It is essential to consider the patient’s coagulation profile, especially if hepatic metastases are present or if the patient has any blood dyscrasias. Once the epidural infusion catheter is placed, it is activated either intra- or postoperatively before the conclusion of anesthesia. A basal rate is usually programmed and may be sufficient for most patients.

The location of the epidural catheter tip is important and should be positioned close to the nerve route level of the dermatome of the surgical incision. For most abdominal surgeries, a catheter placed with the tip at the mid-abdominal dermatomes (e.g., T10) should provide sufficient abdominal coverage, hence thoracic epidurals are preferred to reach the desired dermatomal level. For thoracic surgery, a transcutaneous extrapleural catheter placed under direct videoscopic vision by the thoracic surgeon can be considered, which negates the need for preoperative placement of an epidural catheter. Thoracic epidural placement requires skill and proper training, as the interlaminar space in the thoracic spine is relatively narrow and difficult to access, especially without imaging such as fluoroscopy. For lower limb surgeries (such as amputations), a lumbar catheter should be considered.

Continuous epidural infusion with a set basal rate may be sufficient for most patients. The choice of agents to be infused is based on institution-specific standard protocols, often including a local anesthetic (e.g., bupivacaine or ropivacaine) combined with an opioid (fentanyl or hydromorphone) and occasionally with adjuncts (clonidine and adrenaline). The local anesthetic concentration is chosen to provide only a sensory blockade to allow early postoperative ambulation as part of enhanced recovery pathways. Lidocaine 0.5% or bupivacaine 0.25% provide sensory analgesia, but when combined with an opioid agent, the concentration required is significantly reduced to as little as bupivacaine 0.075%, which offsets the need for postoperative vasopressor support.

A patient-controlled epidural bolus may also be programmed to help a patient with the incidental increase in pain (patient-controlled epidural analgesia; PCEA). It is important to remember that the analgesic effect of a bolus may take several minutes, and it is advisable to educate the patient to use such boluses before any anticipated movements such as going to the bathroom. The duration of the epidural infusion is usually 2–3 days after surgery, before removal of the catheter to avoid infection. A bolus of long-acting, hydrophilic opioids, such as hydromorphone or morphine, should also be considered immediately before epidural catheter removal to extend the duration of analgesia. Catheters may be used for extended periods if the catheter is tunneled subcutaneously in the paraspinal area to minimize the risk of catheter infection.

Single bolus dosing of an epidural is not optimal unless conditions preclude the use of a catheter, such as difficulty in guiding the catheter in the epidural space. Single bolus dosing cannot provide long-term analgesia but may help during the immediate postoperative phase, for example, after lesser surgery, such as for debridement of tissue. A bolus dose that includes long-acting, hydrophilic opioids, for example, hydromorphone or morphine, would ideally suit such single-shot techniques.

Spinal Analgesia

Spinal analgesia is gaining increasing popularity, especially with minimally invasive surgery. Intrathecal opioids are also effective in open abdominal surgery and are accompanied by fewer postoperative complications that often accompany continuous infusions of epidural administered local anesthetic agents in the postoperative period. Intrathecal administration of opioids combined with local anesthetics has been in use for decades. A small amount of intrathecal opioid (e.g., 200 µg of morphine) and adjuncts such as clonidine (e.g., 20–30 µg) may enhance the analgesic effect and duration and help reduce the concentration of the local anesthetic, with dramatic sparing of systemic opioid requirements and reduced sedation in the first 24 h after surgery. Opioid requirements may increase slightly on the second postoperative day. Given the single-shot nature of this technique, the hemodynamic lability accompanying the sympatholytic effect of the local anesthetic agent is managed intraoperatively by the anesthesiologist and is resolved in the postoperative period, with less postoperative hypotension.

Regional Anesthesia

Regional anesthesia is a well-known method for intraoperative and postoperative analgesia. While it may avoid the need for general anesthesia entirely, it may also help reduce postoperative complications from general anesthesia and reduce the recovery time. In patients who are not suitable for neuraxial techniques, for example, due to poor coagulation profiles, spinal metastasis, and so on, a plexus blockade may be utilized with a lower risk of bleeding-related complications. The use of ultrasound has gradually replaced the need for a peripheral nerve stimulator. Ultrasound is considered a safer alternative as blood vessels are visualized and avoided.

Single-shot plexus blockade may be utilized for shorter surgeries, with analgesic effects lasting for several hours depending on the local anesthetic agent used. It is instrumental in ambulatory patients who are expected to be discharged from the recovery room. Continuous plexus blockade is a valuable modality for providing near-complete analgesia for several days. A continuous infusion catheter can remain in situ for 3–5 days. Catheter migration is one of the most common occurrences due to limb movement, hence a secure method such as suturing the catheter is recommended.

Side Effects and Complications

In addition to the type of modality, another critical aspect of postoperative analgesia is the choice of analgesic agent. Opioids are the most common agents used, but other agents, such as NSAIDs, antineuropathic drugs (e.g., gabapentin), and even muscle relaxants, can be used. It is crucial to appreciate the risk-benefit profile of each modality.

Opioids used via the PCA route have side effects similar to those of the oral administration route, including nausea, vomiting, pruritus, sedation, and respiratory depression. The most common side effects are nausea and vomiting, and the addition of antiemetic(s) is a common practice. Female sex, history of postoperative nausea and vomiting or motion sickness, nonsmoking status, younger age, general anesthesia with volatile anesthetics and nitrous oxide, postoperative opioids, duration of anesthesia, and type of surgery (cholecystectomy, laparoscopic, gynecologic) are recognized risk factors for postoperative nausea and vomiting. The recommended pharmacologic agents for the prevention and management of postoperative nausea and vomiting include serotonin (5-HT3) receptor antagonists (ondansetron, dolasetron, granisetron, tropisetron, ramosetron, and palonosetron), neurokinin-1 (NK-1) receptor antagonists (aprepitant, casopitant, and rolapitant), corticosteroids (dexamethasone and methylprednisolone), butyrophenones (droperidol), antihistamines (diphenhydramine and meclizine), and anticholinergics (transdermal scopolamine). Current guidelines do not recommend prophylactic treatment in every patient, but only in the subset of at-risk patients.

Pruritus occurs in about 2%–10% of patients treated with systemically administered opioids. The risk is higher when the neuraxial route is utilized. Opioid-induced pruritus is higher in obstetric patients, with the reported prevalence of opioid-induced pruritus ranging between 60% and 100%. This high prevalence may be due to the interplay between estrogen receptors and opioid receptors. Patients undergoing major orthopedic surgery had a 30%–60% prevalence after intrathecal opioid administration. The type and dose of opioids used, and the method of drug administration, play a role in pruritus. Opioid agonists, such as morphine or methadone, excluding fentanyl or oxymorphone, cause local itching and a typical histamine weal and flare response. However, after intrathecal or epidural administration of opioids, patients typically scratch the nose, perinasal area, and upper part of the face. Facial itching may be explained by high concentrations of opioid receptors in the trigeminal spinal nucleus innervating facial areas. Using lipid-soluble agents (fentanyl and sufentanil), the minimum effective dose and the addition of local anesthetic agents seem to decrease the prevalence and severity of itching. Intrathecal agents such as morphine cause a longer duration of pruritus, which is also more difficult to manage. Medications used to manage pruritis include opioid antagonists such as naloxone and naltrexone, but are known to reduce the analgesic effects of opioids, particularly at higher doses. Nalbuphine effectively prevented and treated opioid-induced pruritus without increasing pain. However, the treatment was associated with increased drowsiness, whereas no reduction in pruritus was observed after subcutaneous injection of 400 µg of naloxone in patients who received intrathecal fentanyl and morphine. Other medications to reduce pruritis include antihistamines (e.g., diphenhydramine and hydroxyzine).

Postoperative confusion may occur, particularly in older patients, due to delayed metabolism and accumulation of drugs, resulting in delirium. However, the treatment of pain may cause delirium. In a large population of patients undergoing noncardiac surgery, higher pain levels at rest correlated with the development of delirium, and the method of postoperative analgesia, type of opioid, and cumulative opioid dose were not associated with an increased risk of delirium. ^,

Epidural analgesia-related side effects include neuraxial hematoma and subsequent spinal cord compression, nerve injury, and infection that may lead to an epidural abscess and cord compression. Risk factors predisposing to neuraxial hematoma include low platelet count, anticoagulant use, and coagulation defects in patients with cancer. Rosero and Joshi reported that in more than 1.3 million nonobstetric epidural analgesic procedures the incidence of spinal hematoma and abscess was 1 per 5401 and 1 per 13,968 catheterizations, respectively. Kupersztych-Hagege et al. reported one spinal hematoma and two spinal abscesses in 2907 patients who underwent lung surgery.

Patients should be monitored for any sign of cord compression or infection in the intraspinal space after placing (or attempting) a neuraxial block (spinal or epidural) or after removing an epidural catheter. Patients should be evaluated daily for any neurologic signs or symptoms that may arise from cord compression. An urgent MRI scan of the spine is essential if a hematoma or epidural abscess is suspected. A CT scan is limited in its ability to identify a collection of fluids. If a spinal hematoma or abscess is suspected, timely (within hours) surgical drainage is essential to avoid long-term neurologic complications. Regular postoperative laboratory investigations can help evaluate a possible infectious process and guide the removal of an infusion catheter.

Other complications include postoperative neurologic deficits, postdural puncture headache, and systemic local anesthetic toxicity. Rare intracranial complications may also follow dural puncture, with the pathophysiology likely linked to intracranial hypotension with subsequent tearing of bridging veins. Predisposing risk factors for a cranial hematoma in obstetric patients, including coagulation disorders, arteriovenous malformations, or multiple punctures, are present in a minority of patients. Close postoperative monitoring for a change in the nature of headaches from postural to nonpostural, prolonged, or onset of focal neurologic signs is recommended.

Postoperative and Postdischarge Follow-up

During the immediate postoperative recovery phase after surgery, patients need to be carefully monitored for excessive sedation due to opioids prescribed for postoperative analgesia. Once intravenous PCA or epidural infusion is discontinued, it is essential to reassess patients to determine if their analgesic requirements are met. As the surgical pain gradually subsides, careful adjustment of the opioid dosage should be made to anticipate hospital discharge. In some patients who are on high doses of preoperative opioids, a reduction in postoperative dosing may occur after surgical resection of the painful part of the tumor or if a painful extremity is removed. This reduction should be titrated before hospital discharge.

Depending on the patient’s pain, increased administration of analgesics may be required for a short period immediately after hospital discharge. A follow-up appointment with a pain physician in patients with significant pain at discharge can help manage long-term analgesic strategies. Some patients would also benefit from attending a transitional pain clinic to identify and manage acute and persistent pain to prevent chronic postsurgical and neuropathic pain.

Conclusion

In summary, considering that patients with cancer may already be on high doses of opioids preoperatively, careful choice of an analgesic modality should consider other comorbid diseases (including abnormal coagulation profile, spinal metastasis, decreased immunologic function, presence of neuropathic disease, and cognitive deficits). Careful choice of analgesic modality should aim to provide excellent postoperative analgesia with minimal or no side effects and related complications.