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Palliative Care - Pain Management - Fast Facts | NEJM Resident 360

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.

In this section, we cover the basics of pain:

• Definition, Types of Pain, and Cancer Pain Syndromes

• Assessment

• Pharmacologic Management

• Nonpharmacologic Management and Complementary/Alternative Therapies

Definition

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.

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 stretch 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 as a side effect of treatment (e.g., chemotherapy-induced neuropathy or radiation). It 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

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)

Cancer-pain syndromes can also be classified as disease-related or treatment-related. 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 a 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.

Nonopioid Analgesic Agents

(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.

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.

Guiding Principles of Opioid Prescribing for Cancer-Related Pain

• When possible and not contraindicated, choose oral agents due to convenience and cost-effectiveness.

• When initiating opioids, start with a low dose of a short-acting agent.

• While direct comparison studies have generally not shown significant differences in efficacy between opioid agents, the appropriate medication and starting dose should take into account a patient’s age, liver and renal function, and prior experiences with opioids.

• Avoid combination products if possible (such as hydrocodone–acetaminophen tablets) to allow for easier titration and to avoid acetaminophen toxicity.

• Severe or chronic cancer pain should be managed with scheduled opioids, often using long-acting or extended-release formulations with as-needed immediate-release opioids for breakthrough or incident pain (often 10%–20% of the total daily requirement of extended-release opioid).

• Most opioids (except methadone and transdermal fentanyl) can be safely uptitrated by 50%−100% after 24 hours if pain is not adequately controlled.

  • Indications that pain is not adequately controlled include use of more than three or four breakthrough doses in 24 hours.

• Opioids have the potential for aberrant use and addiction even in patients with cancer, and long-term use can result in tolerance, dependence, and hyperalgesia.

Commonly Used Opioid Agents

Opioid	Initial dosing	Onset (mins)	Peak Effect (hrs)	Duration (hrs)	Commonly Used Formulations	Comments
Morphine	7.5 or 15 mg PO every 4 hrs	15–20	0.5–1	3–5	Immediate release: 15, 30 mg tablets; Extended release: 15, 30, 60 mg tablets	Avoid in renal disease (renally cleared active metabolite)
Oxycodone	5 mg PO every 4–6 hrs	15–20	1	3–5	Immediate release: 5, 10, 15, 20, 30 mg tablets; Extended release: 10, 15, 20, 30, 40 mg tablets	Second line in renal disease (after hydromorphone)
Hydromorphone	2 mg PO every 4–6 hrs	15–20	0.5–1	3–5	2, 4, 8 mg tablets	Safer in renal and liver disease
Hydrocodone	5–10 mg PO every 4–6 hrs	15–20	0.5–1	3–5	5, 7.5, 10 mg tablets	Most commonly seen in combination pills with acetaminophen
Morphine	2–4 mg IV/SQ every 3–4 hrs	2–5	0.25–0.5	3–5		Avoid in renal disease (renally cleared active metabolite)
Hydromorphone	0.2–0.4 mg IV/SQ every 3–4 hrs	2–5	0.25–0.5	3–5		Safer in renal and liver disease

Abbreviations: PO, by mouth; IV, intravenous; SQ, subcutaneous

(Reference: Acute Care Opioid Table. Pain and Procedural Sedation in Acute Care 2016.)

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.

• 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:

Opioid Equianalgesic Table

• The above 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.

Adverse Effects of Opioids

Side Effect	Management	Notes
Nausea	Antiemetics (avoid ondansetron, which worsens constipation)	Common when initiating opioids but often improves within a few days
Pruritis	Nalbuphine; consider rotating opioids	Mediated by mu receptor; antihistamines are not helpful
Constipation	Prophylaxis with standing bowel regimen (polyethylene glycol and senna); consider peripherally acting antagonists (e.g., methylnaltrexone, oral naloxone) if aggressive bowel regimen not effective	Physiologic tolerance to constipating effects does not occur
Somnolence, mental clouding	Dose reduction or rotation to a different agent	Often improves in several days to weeks
Urinary retention	Bladder catheterization; reduction of other agents; consider alpha-1 antagonists
Myoclonus	Dose reduction or opioid rotation; cautious addition of benzodiazepines (monitor respiratory status)	Can be a sign of neurotoxicity; may precede seizure activity
Respiratory depression	Holding further doses; administer small doses of naloxone if severe or progressive obtundation	Most common with rapid uptitration; also seen in accumulation of active metabolites
Hyperalgesia	Dose reduction or opioid rotation	Paradoxical increase in pain as opioid doses are increased

(Reference: Opioids, Adjuvants, and Interventional Options for Pain Management of Symptomatic Metastases. Ann Palliat Med 2014.)

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.

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