Guideline: Evidence-Based Best Practices for the Management of Cancer-Related Pain

The American Society of Pain and Neuroscience (ASPN) has created a best practice guideline including evidence-based recommendations for the management and reduction of cancer-associated pain. These guidelines were published in the Journal of Pain Research.

Current research indicates that moderate to severe pain is present in roughly 35% of all patients living with cancer; this figure jumps to 80% among patients with advanced-stage cancer. This pain, according to researchers, is the most significant impairment to patient quality of life.

Despite the publication of multiple studies on cancer-related pain management and interventional pain management strategies for this patient population, no widely recognized formal pain management guidelines exist. In 2019, an expert consensus on the management of breakthrough cancer pain in older adults cited this lack of agreement on the integration of interventional pain management techniques as a treatment challenge.

To address this, members of the ASPN came together to create a best practice-based guideline offering evidence-based recommendations for advanced interventional therapies for cancer-related pain.

ASPN members performed a needs-based assessment of both therapeutic efficacy and patient safety relating to interventional pain techniques for cancer related pain, determining that an evidence-based best practice review was necessary. Therefore, a multidisciplinary panel of pain medicine specialists was formed to create these best practice guidelines.

An initial literature search identified a total of 1,032,581 individual manuscripts for review; from there, 89 were selected and the quality of evidence was graded from 1 to 3 with a degree of recommendation provided (scale, A to D or insufficient [I]) based on the US Preventive Services Task Force criteria.

The best practice recommendations and guidelines from the ASPN are outlined below.

Opioids for Cancer Pain

Best practice statements:

• Opioid therapy should be considered to manage moderate to severe cancer-related pain (Evidence evaluation: I-A)
• Opioid selection should be individualized, accounting for variable pain presentation and comorbidities (Evidence evaluation: III-B)

Because cancer-related pain can be moderate to severe in up to 50% of patients, opioids are frequently utilized as a pain management tool. The World Health Organization (WHO) has developed a 3-step “Ladder” for the treatment of cancer pain, first recommending nonopioids, then mild opioids, then strong opioids until pain control is achieved.

Opioid selection should be individualized based on variability in pain presentation and coexisting comorbidities. Both morphine and codeine should be avoided in patients with advanced chronic kidney disease or end-stage renal disease, while hydromorphone and oxycodone can be used with caution; methadone and fentanyl “appear to be safe to use.”

Methadone, meperidine, and codeine should all be avoided in patients with liver dysfunction. Morphine, hydromorphone, oxycodone, and tramadol may require dose adjustments. There have also been reports of increased infection incidences in patients using long-acting opioids with immunosuppressive properties.

Recent Cochrane reviews suggested that although the quality of evidence on opioid use for cancer pain was low, 19 of 20 patients who use opioid therapy experience a meaningful reduction in pain within 14 days. However, most patients will experience adverse events, and between 10% and 20% of patients on opioid therapy may need to change their treatment due to the severity of these side effects.

“Given the potential for opioid use disorder, physicians must remain vigilant and perform careful evaluations and regular follow-up to address key safety concerns when maintaining patients on long-term opioid therapy, particularly given increased survival rates with certain types of cancer,” the researchers wrote.

Adjunct Medications

Methadone

Best Practice Statements:

• Methadone can be considered when other opioids are ineffective or when NMDA or serotonin receptor modulation is desired (Evidence evaluation: II-3 C)
• Dosing should be dependent on opioid tolerance, and low introductory doses should be used for opioid-naïve patients (Evidence evaluation: II-3 B)
• For patients who are opioid tolerant, a conservative approach is recommended. Begin at 75% to 90% less than the calculated equianalgesic dose using 1:15 to 1:20 conversion factor (Evidence evaluation: II-3 A)

Strong opioids are the third step on the WHO analgesic ladder. Methadone is used when patients develop a tolerance to opioids, an intolerance to the side effects, or allergic reactions to strong opioids like morphine. Patients with neuropathic pain in particular may benefit from the dual nociceptive and neuropathic properties.

Initial dosing should be 2.5 mg 3 times daily in those who are opioid naïve, with dose adjustments of 5 mg/d or less every 5 to 7 days. For opioid tolerant patients, conversion should be made to an equianalgesic dose, with 1:2 to 1:20 conversion factor. Maximum starting dose should be 30 mg/d with a dose adjustment of 10 mg/d or less every 5 to 7 days.

Before initiation, providers should assess for cardiac arrhythmia risk through a baseline ECG evaluating for QT interval prolongation.

Based on both a Cochrane review and secondary literature search, there is no evidence comparing methadone to placebo in people with cancer, and the evidence is weak comparing methadone to morphine. Available studies demonstrate “equipotent efficacy in treating mild pain when comparing methadone to morphine or transdermal fentanyl with comparable associated side effects,” the researchers wrote.

Ketamine

Best Practice Statements:

• Ketamine therapy can be considered on a case-by-case basis for the relief of refractory neuropathic, bone, and mucositis-related pain (Evidence evaluation: II-1 B)

Ketamine can be administered via intravenous, intranasal, intramuscular, or oral routes. Side effects are “primarily dissociative in origin” and include dysphoria, hallucinations, evoked nystagmus, and altered perception. Other side effects can include nausea, vomiting, elevated liver enzymes, hematuria, dysuria, hypertension, and tachycardia.

Lower doses of ketamine, careful titration, and concomitant benzodiazepines or alpha-2 agonists can mitigate these side effects.

Patients should be evaluated for cardiovascular and cerebrovascular risk factors prior to ketamine initiation. Continuous hemodynamic monitoring is required for those on an intravenous (IV) protocol.

Evidence on the use of ketamine in cancer pain is limited to “a few” randomized controlled trials with varying results. National comprehensive Cancer Network and European Society for Medical Oncology guidelines recommend the consideration of oral or IV ketamine for refractory pain that does not respond to other analgesics or adjuvants, as well as for patients with central sensitization and for palliative treatment of neuropathic pain.

A 2017 Cochrane review found insufficient evidence to assess ketamine benefits and harms as an adjuvant to opioid therapy for the relief of refractory cancer-related pain.

“There is currently an absence of conclusive evidence for ketamine as an adjuvant analgesic in cancer pain as the data remains mixed,” the researchers wrote.

Radiotherapy, Radioisotopes, and Bone-Modifying Agents for Metastasis

Best Practice Statements:

• EBRT with short, fractionated regimens are favored over conventional schedules for painful metastatic bone disease; SBRT may be preferred in radio-resistant cancers or oligometastatic disease (Evidence evaluation: I-A)
• Osteoclast inhibitors may be used, but have been found to be unhelpful for some cancers (i.e., metastatic non-small cell lung cancer). These agents should be used as an adjuvant treatment and considered on a case-by-case basis.

Metastatic bone disease is a common manifestation of advanced cancer and is a significant source of morbidity. The most common sites of metastases include the spine and sacrum; these patients frequently present with pain, pathologic fractures, and spinal cord compression.

External beam radiation therapy (EBRT) is the most common treatment modality for painful metastatic disease. Research has demonstrated that a single treatment fraction of 8 Gray (Gy) provides equivalent pain relief to conventional 30 Gy treatment delivered in 10 treatment fractions.

Stereotactic body radiation therapy (SBRT) may be preferred for patients with radio-resistant cancers like melanoma, or for those with oligometastatic disease.

The use of radiopharmaceutical therapy is reserved for patients who have failed traditional radiotherapy, as well as for those with polymetastatic disease who are not candidates for palliative radiation. Agents are administered via IV, and selectively irradiate sites of metastatic bone involvement. Samarium-143, strontium-89, and radium-223 are the most commonly used radioisotopes.

Bisphosphonates and denosumab can also be used for painful metastatic disease. A Cochrane review of patients with metastatic breast cancer found that bisphosphonates can significantly improve pain scores. Analgesic potential of osteoclast inhibitors has been questioned, particularly in those with non-small cell lung cancer, and the use of calcitonin to reduce metastatic bone pain is controversial due to the limited evidence supporting its use.

Blocks and Neurolysis

Best Practice Statements:

• Celiac plexus neurolysis can be performed for pancreatic cancer-related moderate to severe abdominal pain refractory to analgesics (Evidence evaluation: I-A)
• Splanchnic neurolysis can be considered in patients with abdominal cancer-related pain stemming from advanced body and tail located pancreatic cancer (Evidence evaluation: I-B)
• Early neurolysis is associated with better outcomes (Evidence evaluation: II3-B)
• Superior hypogastric plexus neurolysis should be considered in patients with intractable pelvic cancer-related pain (Evidence analysis: II-B)
• Ganglion impar neurolysis should be considered in those with intractable perineal cancer-related pain (Evidence analysis: III-B)

Both sympathetic blocks and neurolysis are utilized frequently for intractable visceral cancer-related pain. Multiple neural structures may be targeted, based on the location of either the primary malignancy or distant metastasis responsible for the pain.

Celiac Plexus

Numerous posterior percutaneous approaches for celiac plexus neurolysis have been described, including transaortic, retrocrural, and splanchnic. Intraoperative approaches have also been described.

Potential complications associated with targeting the celiac plexus include retroperitoneal hematoma, local anesthetic toxicity, renal injury, and pneumothorax. The risk of potentially serious neurological complications, though, is less than 1%.

A systematic review found that percutaneous celiac plexus neurolysis can significantly improve pain in patients with upper abdominal cancer, along with a concomitant decrease in opioid consumption and side effects. A randomized controlled trial found that patients randomized to celiac neurolysis prior to step 2 on the WHO analgesic ladder experienced better pain control and quality of life vs those who received celiac neurolysis after failing to achieve analgesia on step 3 of the analgesic ladder.

Results of another randomized controlled trial suggest that splanchnic neurolysis has superior results vs celiac plexus neurolysis for pancreatic body and tail cancer.

Superior Hypogastric Plexus

Between 70% and 90% of patients have been found to achieve significant pain relief following superior hypogastric plexus neurolysis. In a recent large retrospective study, patients achieved a 48% visual analogue score decrease and 55% decrease in opioid consumption, persisting at 3 months.

Two recent review articles indicated that although there are “many safe and efficient ways to block the superior hypogastric plexus,” there have been few large, prospective, randomized studies to prove efficacy. Newer data continue to highlight the potential benefits of this practice for malignant pelvic pain.

Ganglion Impar Block

Ganglion impar nerve block was first described in 1990 and initially used to treat sympathetic pain of malignant origin. Since then, it has been used to treat nonmalignant forms of pain, including intractable perineal pain and coccygodynia, as well as intractable pain associated with rectal, anal, vulvar, and other perineal cancers.

Data on the efficacy of neurolytic ganglion impar block in those with cancer patients is limited to case reports and series, but these reports have consistently demonstrated improved pain and no significant adverse events.

Complications are infrequent and include motor, sexual, bladder, and bowel dysfunction and perforation of the rectum.

Randomized controlled trials are lacking, but data have shown ganglion impar blocks to be safe and effective in treating pain.

Epidural and Intrathecal Analgesia

Best Practice Statements:

• Intrathecal drug delivery via an implantable pump should be “strongly considered” in patients with cancer related pain that does not respond to, or that results in side effects, from conventional medication management (Evidence evaluation: I-A).
• Trailing prior to intrathecal pump implantation for cancer-related pain is at the discretion of the physician and patient, and is not a requirement (Evidence evaluation: III-C).

Intrathecal analgesia via implanted pump is indicated when pain is severe despite “adequate trials of conventional medication” or when dose-limiting side effects are experienced. Multiple studies have demonstrated analgesic efficacy and reduction of side effects.

Trialing practices are controversial and have “questionable utility in the cancer pain setting.” Recent guidelines have indicated that trialing should be optional; no prospective studies support trailing in cancer pain, and recent studies of IDD in cancer pain “typically did not trial.”

Level I evidence supports the efficacy of IDDS, and there is compelling cost-effectiveness data. Trialing should be considered discretionary and be based on factors like clinician preference, patient population, referral patterns, and payor environment.

Trialing may, in certain situations, have utility to help assess individual painter response to therapy inclusive of analgesia, side effects, functional improvement, and appropriate starting dose.

In patients with cancer-associated pain, it is impractical and unethical to taper systemic opioids prior to pump implant. Literature supporting IDD in the cancer setting dose not discuss the tapering of systemic opioids prior to implantation.

Hospital admission should be arranged in situations where systemic opioids are causing concerning levels of sedation.

The two most popular and commercially available variable rate pumps are peristaltic continuous pumps and valve-gated pumps.

Three medications have been approved by the FDA for intrathecal use: morphine, ziconotide, and baclofen. Other medications—fentanyl, hydromorphone, bupivacaine, and clonidine—have all been commonly and safely used as well. Off-label drugs should be tried only after FDA-approved drugs are attempted and failed, or are contraindicated.

Starting intrathecal opioid doses vary widely. Research suggests that the initial daily dose should be calculated using a ratio of 100:1 of the patients’ daily oral morphine equivalent. Physicians should also consider risk of cardiopulmonary depression and hospital admission when calculating dose. Conservative dosing strategies are typically recommended.

Pharmacological complications include cardiopulmonary depression, anaphylaxis, and meningitis. Other rare potential complications include catheter tip granuloma formation, bleeding complications, infection risk, and those related to surgical management. Adverse effects include opioid-induced hyperalgesia, hypotension, inflammatory mass, hypogonadotropic hypogonadism, immunologic compromise, headaches, seromas, hygromas, and bacterial meningitis.

Patients with cancer are likely to undergo radiation and chemotherapy that may experiences negative impacts on IDD. There are many safety factors to consider, including absolute neutrophil count greater than 500 µL and platelet counts greater than 80,000 µL.

While epidural or spinal metastases are “not an absolute contraindication to placement of IDDS,” these lesions may affect the efficacy of the device and increase complication rates associated with neuraxial treatments.

Formation of intrathecal catheter tip granulomas may result in “potentially irreversible” neurology sequelae; the prevalence of this complication is as high as 8%. Morphine, hydromorphone, sufentanil, bupivacaine, and baclofen may contribute to formulation of catheter tip granulomas. MRI with and without contrast, CT myelogram, or dye studies can be used to detect granulomas.

Pocket and lumbar site infections, meningitis, and encephalitis are the primary infection concerns associated with IDD. Cancer treatments—including corticosteroids and chemotherapy—may increase the risk for surgical site infections; current infection risk is between 0.7% and 3.2% per year.

Surgical and technical complications include postdural puncture headache, occurring in 15.5% of patients, and CSF hygromas in 1.5%. Pocket site seroma is also common and can be managed conservatively via pressure dressing and abdominal binder.

The most common complications following IDD implantation are catheter-related malfunctions, including catheter tip migration, kinking, occlusion, fracture, and loosening of connections. Incidence rates of catheter migration, tear, and occlusion are 7.3%, 6.4%, and 1.8%, respectively. Pump complications like motor stalls, over or under infusion, corrosion, and gear wear may occur, albeit to a lesser degree. Incidence of motor stall is 0.28% at 48 months and 0.69% at 84 months after implantation.

MRI can be necessary in ongoing cancer treatment, and the most commonly utilized intrathecal pump systems have MRI Conditional labelling. These pumps are compatible with MRI when specific parameters laid out by device manufacturers are followed.

Spinal Cord Stimulation

Best Practice Statements:

• Spinal cord stimulation can be considered in patients with refractory cancer pain (Evidence evaluation: II-3-C)
• Spinal cord stimulation may be considered on a case-by-case basis for pain stemming from cancer treatment, i.e., chemotherapy-induced peripheral neuropathy (Evidence evaluation: III-C)

Complex regional pain syndromes type I and II, postlaminectomy syndrome, chronic radiculopathy, intractable neuropathic pain, and visceral pain are the most common indications for spinal cord stimulation (SCS).

“While treatment of cancer-related pain is often focused on symptoms explicitly related to the primary malignant diagnosis,” the authors wrote, “true supportive care and palliative care should include all treatments that may improve [quality of life].”

The adverse effects of many cancer treatments are “amenable” to SCS. Due to the increase in 5-year cancer survival rates over the past 2 decades, more patients than before are living with chronic pain stemming from effective cancer treatments. For example, 52% of patients exposed to neurotoxic chemotherapeutic agents develop chemotherapy-induced peripheral neuropathy (CPIN); many case reports have demonstrated the efficacy of SCS in treating CPIN, but there are no randomized controlled trials showing the same results.

Patients may require screening MRI to identify disease progression or evaluate new symptoms prior to SCS. Before devices are selected, providers should understand the MRI conditionality of the devices, and additional consideration should be made for the degree of patient comfort in “maintaining, charging, and programming” the implantable pulse generator.

Vertebral Augmentation and Radiofrequency Ablation

Best Practice Statements:

• Vertebral augmentation should be “strongly considered” for patients with symptomatic vertebral compression fractures due to spinal metastases (Evidence evaluation: I-A)
• Percutaneous radiofrequency ablation with or without cement augmentation is a safe, effective palliative therapy indicated to treat severe back pain due severe back pain due to spinal tumors. (Evidence grade: II-2-B)

Up to 30% of all newly diagnosed cancers include vertebral metastasis at presentation, and between 30% and 70% of patients will present with back complaints due to metastasized spinal tumors. Clinical manifestations include localized pain, neurological deficits, and spinal deformities. Appropriate management requires multi-disciplinary treatment approaches, including assessment of cancer staging, tumor involvement, spinal instability and deformities, neurological function, the number of involved levels, radio- and chemo-sensitivity of the tumor, and patient prognosis.

Vertebral augmentation can be considered for patients with severe pain secondary to pathological vertebral compression fractures. Percutaneous radiofrequency ablation with or without cement augmentation is indicated for the treatment of back pain due to spinal tumors and has been demonstrated as a safe, effective palliative therapy.

Radiofrequency Lesioning and Nerve Blocks

Best Practice Statements:

• Radiofrequency lesioning of the dorsal root ganglion can be considered in the treatment of axial thoracic back pain from vertebral malignant metastases (Evidence evaluation: I-C)
• Application of nerve blocks via corticosteroid or radiofrequency lesioning can be considered for cancer pain unresponsive to medical management (Evidence evaluation: II-2 C)

Radiofrequency ablation and nerve blocks are the most studied in the context of nonmalignant pain treatment. In current cancer literature, there have been case reports and series demonstrating pain relief efficacy in conditions that arise from metastatic brachial plexus tumors, head and neck cancer, thoracic vertebral body metastases, and glossopharyngeal neuralgia.

Surgical Options

Best Practice Statements:

• Cordotomy should be considered for patients with uncontrolled unilateral nociceptive pain after the failure of more conservative options (Evidence evaluation: II-B)
• Myelotomy is used for infradiaphragmatic visceral pain for pain control and to decrease opioid consumption (Evidence evaluation, III-C)
• (Dorsal root entry zone)DREZ-otomy is indicated for focal limb pain and in Pancoast tumors (III-Insufficient)
• Cingulotomy is indicated for late-stage, uncontrolled pain refractory to other therapies (Evidence evaluation, III-C)

Surgical interventions—including CT guided radiofrequency cordotomy, myelotomy, DREZ-otomy, and cingulotomy—can be considered in carefully selected patients to manage refractory cancer pain.

In a study of cordotomy, 85.7% of patients achieved higher than 33% pain relief vs those in the palliative care group. At 1 week, 77.9% of patients in the palliative care group opted to undergo cordotomy, and also received a greater than 33% reduction in pain. Case series have also demonstrated high overall pain control, with between 80% and 100% of patients reporting no pain at 1 month.

At late disease stages, if all therapeutic options have failed, stereotactic anterior cingulotomy can be effective in controlling pain; however, this comes with cerebral risks, psychological side effects, and cognitive impairment.

Intrathecal Resiniferatoxin

Best Practice Statements:

• Resiniferatoxin is undergoing safety and efficacy trials. A grade for this treatment is insufficient.

Resiniferatoxin (RTX), derived from the Euphorbia resinifera plant, is a potent agonist for transient receptor potential vanilloid 1 nerve fibers. In the first human RTX study—a single-center, Phase 1b, nonrandomized, open-label, dose-escalation study—a population of patients with severe refractory pain due to advanced malignancy at or below chest level underwent intrathecal RTX injection. Lower doses of 3 to 13 µg were associated with variable pain relief and permitted dose escalation up to 26 µg RTX into the intrathecal space.

There is currently an ongoing, multicenter, open-label, Phase 1b trial evaluating the safety and maximally tolerate dose of epidural RTX to treat intractable cancer-related pain. Primary outcome is the dose limiting toxicity and maximum tolerated dose; secondary outcomes are NRS, Brief Pain Inventory Short Form, and daily analgesic consumption.

Initial human safety and efficacy data are promising in reducing the burden of cancer-related intractable pain with minimal adverse events, and a multicenter, blinded, controlled, Phase 3 clinical trial is ongoing.

Limitations of the current guidelines include confinement to the limitations of available data and methodological differences in studies, inclusive of study design and study population heterogeneity.

“This paper bridges the gap between conservative medical management and recently published surgical neuroablative guidelines,” the researchers concluded. “We provide clear evidence-based guidance and recommendations on how interventional techniques should be integrated into the management of cancer-associated pain.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Aman MM, Mahmoud A, Deer T, et al. The American Society of Pain and Neuroscience (ASPN) best practices and guidelines for the interventional management of cancer-associated pain. J Pain Res. 2021;14:2139-2164. doi:10.2147/JPR.S315585