Pain Management

Pain is an unpleasant sensation that evolved as an adaptive response to alert an individual to actual or potential tissue damage. Although the utility of nociception (pain sensation) is to avoid injury, pain can also be a maladaptive process (e.g., neuropathic pain and chronic pain syndromes).

Pain also includes an emotional and psychological experience beyond the physical sensation itself. Patients with a significant pain burden frequently suffer socially and spiritually. Uncontrolled pain often affects functional abilities as well as social interactions. Among patients with cancer, the prevalence of cancer-related pain can be as high as 50% and can exceed 60% among patients with advanced or metastatic disease.

Pain assessment and management is a broad topic. Within palliative medicine, pain management most often involves cancer-related pain. Management of other pain syndromes and pain-related diseases are covered in other guides (see chronic noncancer pain, migraine, low back pain). Although palliative physicians do treat patients with these other pain syndromes, they often do so in conjunction with other medical subspecialists. The primary focus of this section is cancer-related pain:

• Types of Pain

• Cancer Pain Syndromes

• Assessment

• Pharmacologic Management

• Nonpharmacologic Management and Complementary/Alternative Therapies

Types of Pain

Pain is often divided into the broad categories of nociceptive and neuropathic pain, based on the underlying pathophysiology. Patients frequently present with a combination of nociceptive and neuropathic pain.

Nociceptive pain is the body’s response to tissue injury via the somatosensory nervous system.

• Somatic nociceptive pain results from insult to bone, joints, or muscles. It is often easily localized and described as aching, stabbing, throbbing, or pressure-like.

• Visceral nociceptive pain is caused by damage to internal organs that are innervated by visceral sensory fibers. It is less often easily localized and can refer pain to other locations in the body when involving shared neuronal pathways with somatic fibers.

  • Visceral pain can arise from dilation of hollow bowel lumen causing cramping or gnawing pain or can be aching or stabbing when caused by stretching of abdominal organ capsules or irritation of the pericardium or pleura.

• Inflammatory pain is classified as a subtype of nociceptive pain characterized by peripheral inflammation. Based on which tissues are involved, inflammatory pain can be somatic or visceral.

Neuropathic pain is caused by abnormal sensory processing and signaling and can arise from either peripheral or central somatosensory malfunction. Neuropathic pain is common in cancer patients, caused by either primary disease (e.g., tumor invasion of major peripheral nerves) or an adverse effect of treatment (e.g., chemotherapy-induced neuropathy or radiation).

• Neuropathic pain is commonly described as burning, electrical, or pruritic but may also manifest as an aching or throbbing sensation.

• Allodynia (pain caused by a stimulus that does not normally cause pain) and hyperalgesia (increased sensitivity to pain from a painful stimulus) can be associated with neuropathic pain.

Cancer Pain Syndromes

Acute cancer pain syndromes: Malignancies are frequently associated with a constellation of symptoms that can be recognized as a cancer pain syndrome. Some examples of acute cancer pain syndromes include:

• pain related to procedural interventions for diagnostic (e.g., biopsy) or therapeutic purposes (e.g., indwelling-catheter insertion)

• tumor-related, as seen in pathologic fractures, malignant bowel obstruction, or spontaneous tumor hemorrhage

• treatment-related, such as chemotherapy-induced mucositis or palmar-plantar erythrodysesthesia (“hand-foot syndrome”)

• referred pain, experienced at a location distant from the site of origin (such as an abdomen-based process causing shoulder or back pain)

Disease-related cancer-pain syndromes are due to direct action of an invading tumor on surrounding tissue and nerves and can be further classified as neuropathic, somatic nociceptive, or visceral nociceptive syndromes. Some examples include:

• neuropathic pain from tumor compression presenting as cranial nerve neuralgias, brachial or cervical plexopathies, or peripheral mononeuropathies

• somatic nociceptive pain from tumor invasion into bone, tumor invasion into soft tissues, or paraneoplastic syndromes such as hypertrophic osteoarthropathy

• visceral nociceptive pain from tumor invasion into visceral organs, such as hepatic capsular distention, peritoneal carcinomatosis, or malignant perineal pain

Treatment-related cancer-pain syndromes are the result of chemotherapy, radiation, or surgery. Some examples include:

• chemotherapy-induced peripheral neuropathy or fractures due to steroid-induced osteomalacia

• radiation-induced plexopathy, myelopathy, proctitis, or enteritis

• postmastectomy pain syndrome or phantom limb pain after amputation

Assessment

A comprehensive pain assessment includes an evaluation of the physical, psychological/emotional, social, and spiritual experience of pain. Several validated formal assessment tools exist to assess the multidimensional aspects of pain, including the Brief Pain Inventory, the McGill Pain Questionnaire, and the Memorial Pain Assessment Card. Whenever possible, identifying the underlying etiology of pain can be important for prognosis as well as treatment.

The initial assessment of pain should include the following:

• intensity or severity

• quality or character

• location and radiation

• temporality (onset, duration, and constant versus intermittent)

• relieving and provoking factors, including response to prior treatments

• associated symptoms

• impact on level of functioning, social interactions, and quality of life

Pharmacologic Management

The overall goal of pain management in palliative medicine is to maximize quality of life and level of functioning. In addition to treating pain with analgesic medications, management may include:

• identifying reversible processes with relevant diagnostic tests (including imaging) that are defined within a patient’s goals of care

• targeting therapies toward reversible processes, including invasive procedures when indicated

• when an underlying disease process is not reversible, treatment modalities that will most effectively target the underlying process (e.g., radiation therapy for painful bony metastases or systemic chemotherapy to reduce tumor burden)

Nonopioid Analgesics

Palliative medicine utilizes several nonopioid analgesics as first-line or adjuvant treatment of pain. A nonopioid analgesic is sometimes sufficient for pain management or is beneficial as an adjuvant analgesic. These agents vary by class, mechanism of action, indications, and contraindications, summarized in the table below.

(Source: Nonnarcotic Methods of Pain Management. N Engl J Med 2019.)

Additional notes:

• The maximum daily dose for acetaminophen is lowered to a maximum daily dose of 3000 mg for adults over the age of 65, and patients with cirrhosis may take up to a daily dose of 2000 mg.

• Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that is a selective inhibitor of the COX-2, which in theory reduces the risk of peptic ulcer disease and bleeding; however, celecoxib carries the same contraindications in renal and cardiovascular disease as other NSAIDs.

• Diclofenac gel is a topical NSAID that can provide local tissue concentration of NSAID with minimal systemic absorption and can be used for mild-to-moderate musculoskeletal pain.

• Although both gabapentin and pregabalin are effective in treating neuropathic pain, increasing reports suggest aberrant use, especially as off-label prescribing has increased.

• Other nonopioid analgesics such as the N-methyl-D-aspartate (NMDA)-receptor antagonist ketamine, are sometimes used for refractory pain, but require close clinical monitoring from a palliative care or pain specialist.

Opioids

Opioids are commonly used in cancer patients when nonopioid analgesics do not provide adequate pain relief or use of nonopioid analgesics is contraindicated. The goals of opioid analgesics are to maximize analgesia and improve a patient’s level of functioning and quality of life while minimizing adverse effects.

Opioids exert analgesic effects by binding to opioid receptors in the peripheral and central nervous systems. The mu opioid receptor and its agonists have been most commonly implicated in the analgesic effects of opioids, and mu opioid-receptor antagonists (e.g., naloxone) prevent or reverse these analgesic effects.

Less frequently used opioids for pain management in palliative medicine:

• Fentanyl is a highly potent lipophilic opioid that is available in a transdermal patch dosed every 2−3 days (a transmucosal formulation is not yet widely used). Fentanyl is also available as an intravenous analgesic. It is the safest agent for use in patients with combined renal and liver disease.

  • The transdermal fentanyl patch must be used with caution in patients who are at risk for elevated body temperature (e.g., fever, use of warming blanket), because high temperatures can lead to cutaneous vasodilation and more-rapid fentanyl absorption, which increases the risk of respiratory depression. Patches also contain metal and must be removed prior to undergoing MRI.

• Methadone is unique among mu opioid agonists because it has a long duration of analgesia and acts as a partial N-methyl-D-aspartate (NMDA) antagonist. Although it can be used as a traditional opioid analgesic, methadone is also effective in treating neuropathic pain. It is safe in patients with renal disease because it does not have active metabolites and is fecally cleared. However, the following features of methadone complicate its use by inexperienced clinicians:

  • It must be carefully titrated due to its variable biphasic half-life.

  • It can prolong the corrected QT (QTc) interval, especially when used in conjunction with other QTc-prolonging agents.

  • It is metabolized by the cytochrome P-450 enzyme CYP3A4, and levels can be influenced by CYP3A4 inhibitors and inducers.

• Buprenorphine is a unique opioid with mixed agonist-antagonist activity (a partial mu/delta-receptor agonist and full kappa-receptor antagonist). As a result, buprenorphine is associated with a lower risk for significant respiratory suppression. It is also safe in patients with renal disease because it undergoes hepatic metabolism. Providers historically required a waiver to prescribe buprenorphine, but this is no longer necessary. Several formulations of buprenorphine, including transdermal and buccal, are FDA-approved for chronic pain management.

• Tramadol and tapentadol are mu opioid-receptor agonists and also inhibit serotonin and norepinephrine reuptake in the central nervous system. Both agents have relatively limited evidence of effectiveness in the treatment of cancer pain, have safety concerns with drug-drug interactions, and tramadol has been associated with serotonin syndrome and seizures.

Opioid rotation: Patients taking opioids may need to switch from one opioid to another. Common indications for rotating opioids include:

• liver or renal dysfunction (acute or chronic)

• intolerable adverse effects or toxicity

• agent only available by one route (e.g., oxycodone is only oral)

• poorly controlled pain despite escalating doses

• hyperalgesia or toxicity

• insurance coverage

Switching from one opioid to another requires accurate conversion between agents with the use of online calculators or an opioid equianalgesic table. The following opioid equianalgesic table displays the morphine-equivalent doses of commonly used opioids.

• For example, 30 mg of oral morphine is roughly equivalent to 20 mg of oxycodone and 1.5 mg of intravenous hydromorphone.

• When rotating opioids, it is important to dose-reduce by 25%−50% to account for incomplete cross-tolerance, because patient response varies to the different opioids.

• Rotating to transdermal fentanyl or methadone is considerably more complicated than standard opioid rotations and requires a palliative care or pain specialist for safe and effective dosing.

See an infographic from NEJM Knowledge+ on rotating opioids.

Adverse effects: Opioids are associated with a range of adverse effects. Some adverse effects appear with the initiation of opioids and improve with continued use. Others require long-term monitoring and management.

Nonpharmacologic Management and Complementary/Alternative Therapies

Because pain is a complex symptom that can have social, emotional, and spiritual components, patients may benefit from treatments focused on its nonphysical aspects.

• Psychological and behavioral interventions such as coping-skills training and cognitive behavioral therapy can help manage the depression, anxiety, and demoralization that can accompany cancer-related pain.

• Physical therapy and rehabilitation therapies may also improve cancer-related pain by targeting associated fatigue and deconditioning.

• Complementary and alternative therapies for pain control include acupuncture, meditation, yoga, music and art therapy, massage, chiropractic, guided imagery, and biofeedback. These modalities are used by patients with chronic cancer-related pain and noncancer pain. Individual patients may derive benefit from these therapies; however, supportive data are lacking.