How Are Adjuvant Medications Such as Corticosteroids and NSAIDs Used for Pain Management?

Introduction and Scope of the Problem

Pain is perhaps the most feared and persistent symptom in palliative care, affecting a major proportion of patients in this setting. Corticosteroids and nonsteroidal anti-­inflammatory drugs (NSAIDs) are frequently used to manage mild to moderate pain or as adjuvant analgesics with opioids for severe pain and are among the most widely used medications in the world. As a class of pharmaceutical agents with antipyretic, anti-inflammatory, and analgesic effects, the NSAIDs include salicylates, p -amino phenol derivatives, propionic acids, acetic acids, enolic acids, and selective cyclooxygenase-2 (COX-2) inhibitors. Corticosteroids operate in a pharmacologically different manner and include several common medications, including hydrocortisone, dexamethasone, prednisone, prednisolone, and methylprednisolone. In addition to pain, corticosteroids are used to alleviate various other symptoms, including anorexia and cachexia, nausea and vomiting, malignant bowel obstruction, and immune-mediated side effects in the palliative care setting. Their application as co-analgesics has been described for the treatment of painful bone metastases as well as relief of symptoms resulting from brain tumors and metastases, spinal cord compression, or superior vena cava syndrome in people with advanced cancer. For patients nearing the end of life, physicians often prescribe corticosteroids to help increase appetite, reduce nausea, improve energy and mood, and enhance a person’s overall sense of well-being.

Relevant Pathophysiology

NSAIDs share a common set of therapeutic properties; principal among these are their ability to reduce edema, erythema, and pain associated with inflammation and to reduce fever. The analgesic effect is attributed to three mechanisms: inhibition of prostaglandin synthesis, inhibition of the release of inflammatory mediators from neutrophils, and a central effect that may involve the N -methyl- d -aspartate (NMDA) receptor. The effectiveness of NSAIDs is due to inhibition of the cyclooxygenase (COX) enzyme. This enzyme has two distinct isoforms: COX-1, which plays an essential role in normal gastrointestinal and platelet function; and COX-2, which is induced in the presence of inflammation and is now understood to play a role in maintaining function.

A summary of commonly used NSAIDs is presented in Table 7.1 . Traditional “nonselective” NSAIDs inhibit both COX isoforms; however, a newer class of selective NSAIDs that specifically inhibit COX-2 has gained favor in recent years. Largely, the beneficial anti-inflammatory and analgesic actions of NSAIDs have been thought to be associated with COX-2 inhibition, while adverse effects were attributed to COX-1 inhibition. Although it was attractive to hypothesize that an agent specifically inhibiting COX-2 might provide analgesia without the adverse effects associated with traditional NSAIDs, mixed evidence suggesting possible increased risk for cardiovascular events with selective COX-2 inhibitors demonstrates a more complex picture.

Corticosteroids are hormonal agents that bind to the glucocorticoid receptor to regulate glucose metabolism. They provide analgesia by blunting the inflammatory response via (1) inhibiting the synthesis of prostaglandin and (2) reducing vascular permeability. Because they are lipophilic molecules, corticosteroids can cross the blood–brain barrier. Steroid receptors in the central and peripheral nervous systems help control neuron growth, differentiation, development, and plasticity. Corticosteroids can reduce neuropathic pain by reducing spontaneous discharges in an injured nerve.

Summary of Evidence Regarding Treatment Recommendations

The WHO Three-Step Analgesic Ladder provides the most universally accepted approach to pain management and analgesic use in palliative care. The first step of the WHO ladder addresses the treatment of mild pain, for which the WHO recommends use of a nonopioid, in particular, an NSAID or acetaminophen, with or without an adjuvant analgesic. The subsequent two steps of the WHO ladder (mild to moderate pain, moderate to severe pain) suggest the addition of an opioid to control pain of increasing severity. Adjuvant medications, including corticosteroids, are advocated at all steps if they directly reduce pain, reduce pain in conjunction with opioid drugs, allow for analgesia at a lower opioid dose, or aid in the management of other concurrent symptoms such as nausea and vomiting, anorexia, immune-mediated diarrhea, and malignant bowel obstruction.

NSAIDs have several advantages over opioid and other nonopioid pain medications. Certain disadvantages, however, may limit their utility. The analgesic effect of NSAIDs has a dose-related ceiling, and NSAIDs are generally only effective for milder pain because they cannot be titrated past safe maximum doses. To treat moderate to severe pain, they generally must be combined with an opioid. NSAIDs carry a risk for potentially serious side effects, including gastrointestinal irritation and bleeding and kidney injury, particularly with chronic use. Additionally, although some NSAIDs are available in parenteral formulations, these are often difficult to obtain. Topical formulations have become increasingly used for localized pain, in particular for acute musculoskeletal pain and localized neuropathic pain, due to their propensity to achieve therapeutic concentrations at the site of pain while potentially avoiding systemic toxicities. However, topical NSAIDs appear to be most effective for short-term use, showing analgesia equivalent to placebo after 2 weeks of use.

Strong evidence to support the use of NSAIDs for management of malignant pain is lacking. A systematic review of 42 trials to assess the safety and efficacy of NSAIDs alone and in conjunction with opioids for the treatment of cancer-related pain, studied NSAIDs versus placebo, compared different NSAIDs to one another and to opioids or combination therapies. Efficacy was demonstrated in seven of eight trials, in which single doses of an NSAID were superior when compared with placebo. Of 14 studies comparing combination of NSAIDs and opioid versus either drug alone, 13 found no or minimal differences in analgesic effect; comparisons between various NSAIDs plus opioid combinations were inconclusive. Another Cochrane review highlighted the lack of evidence to support or refute the use of NSAIDs alone or in combination with opioids for children and adolescents with cancer.

Despite the widespread use of corticosteroids in palliative care, minimal evidence has been published that supports or refutes their use to alleviate pain or other symptoms in this population. A Cochrane review of six studies of corticosteroid use in pain for cancer patients showed an average reduction in pain scores of 0.84 (CI 0.30–1.38) after 1 week of use. Several other studies showed overall improvement in pain but did not use a numeric scale. Unfortunately, due to heterogeneity of studies, specific pain types, medications, doses, or adverse outcomes could not be evaluated.

Common evidence-based uses of corticosteroids in cancer pain management include care of patients with brain metastases, in which corticosteroids are used to reduce intracranial pressure and control or prevent headaches related to cerebral edema, and as analgesic adjuvants for patients with spinal cord and vertebral metastases, especially in the setting of cord compression. Currently, the evidence base and expert consensus support consideration of corticosteroids as a co-analgesic for palliative care patients with certain neuropathic pain syndromes (e.g., sympathetic dystrophies); cancer pain including bone pain, tissue or visceral infiltration, or nerve compression; headache resulting from increased intracranial pressure; and pain and intestinal function related to bowel obstruction. Additionally, corticosteroids have been shown to improve bone pain related to radiation therapy. Although supporting published literature is less available, other common pain syndromes that may benefit from corticosteroids include the pain of stretching of the hepatic capsule from rapidly enlarging liver metastases or acute involution of a necrosing metastatic mass.