Non-Opioid Pharmaceutical Treatment of Cancer Pain
Pharmacotherapy continues to be the cornerstone of cancer pain management (Part 1 and Part 2). The art of cancer pain management is choosing the specific medications that have dual usage or indications for maximizing the beneficial effects of rational polypharmacy without resulting in adverse drug interactions, side effects, and organ toxicity.1 Effective cancer pain treatment improves outcomes with decreased morbidity, improved function, reduced anxiety and depression, and a higher quality of life.2,3 One also must be mindful of polypharmacy, drug–drug interactions, and systemic side effects—particularly in the elderly—when combining these adjunctive medications.4 All medications prescribed should be used with caution, particularly if they are given “off label,” and with informed consent, the risks and benefits assessment must be discussed with the patient and caregiver prior to treatment.
The non-opioid analgesics include a diverse group of medication classes including acetaminophen (APAP), non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antidepressants, anticonvulsants, topical analgesics, hypnotics, muscle relaxants, cannabinoids, N-Methyl-D-aspartate (NMDA) receptor antagonists, and others. In general, nociceptive pain can be responsive to NSAIDs, corticosteroids, and opioids; and neuropathic pain can be responsive to topical anesthetics, antidepressants, anticonvulsants, and opioids (at higher doses). Most of the adjunctive medications discussed in this paper are based on non-malignant pain, clinical experience, and expert opinion, along with cancer pain guidelines (which generally emphasize opioid management).5-7
APAP is commonly used as a first-line analgesic and antipyretic, and is available over the counter. For acute pain, the maximum APAP dose is 4,000 mg per day in healthy adults (3,000 mg daily in elderly adults),8 although it is currently limited to 2,600 mg per day for chronic usage due to an increased risk of renal insufficiency as the result of its effects on prostaglandins.9 One should reduce the maximum dose by 50% to 75% in patients with liver disease including metastasis or hepatitis, or in those with a history of alcohol abuse.10 Recent reports also suggest an increased risk of hearing loss,11,12 and renal carcinoma13,14 with chronic usage. APAP is often coupled with schedule III opioids for a synergistic analgesic effect. In 2011, the FDA urged manufacturers of these products to limit the amount of acetaminophen to 325 mg per tablet (ie, Vicodin, Lortab, Norco, Primlev [300 mg APAP], and Percocet).15 In addition, there are newer formulations of APAP, including intravenous (IV) APAP (Ofirmev, approved in 2010), an elixir, and a rectal suppository. APAP should be preferred over NSAIDs when used in combination with World Health Organization (WHO) step III opioids because of a more favorable side-effect profile, but its efficacy is not well documented.5
NSAIDs may be added to WHO step III opioids to improve analgesia or reduce the opioid dose required to achieve analgesia. Generally, the analgesic and antipyretic effects of NSAIDs can be obtained at lower doses, and the anti-inflammatory effects at higher doses. Studies show little difference between individual drug effectiveness.10
NSAIDs are particularly effective at treating bone metastasis and pathologic fractures,4,5 although they may have an inhibitory effect on boney healing. IV formulations of ibuprofen (Caldolor) and ketorolac (Toradol) are available, as well as an intranasal formulation of ketorolac (Sprix). With IV ketorolac, studies have found that there is better overall analgesia and a slower opioid escalation in cancer patients in comparison to patients treated with opioids alone.16 Any pain generator(s), including visceral pain, seemed to be equally sensitive to NSAIDs.
The continued use of NSAIDs, however, should be restricted because of the risks of serious adverse effects, in particular in elderly patients and those with gastrointestinal (GI), renal, hepatic, or cardiac disease. It is recommended that patients at greater risk for GI toxicity take NSAIDs with a proton pump inhibitor or histamine 2 blockers. Cyclo-oxygenase 2 selective medications (ie, celecoxib, Celebrex) have a similar analgesic efficacy, but are safer in older patients with all GI comorbidities, lower GI bleeding risks, or those on anticoagulants or anti-platelet regimens.17 They can be used preoperatively and postoperatively since they do not affect platelet aggregation, and have been used for pre-emptive analgesia. Because NSAIDs are metabolized in the liver, they may be subject to drug–drug interactions in patients with cytochrome P 450 (CYP450) defects.
Salicylated NSAIDs have fewer anti-platelet effects, comparable to celecoxib (which is contraindicated with a sulfa allergy). Based on cardiovascular morbidity meta-analysis, naproxen has shown a lower risk, with ibuprofen and celecoxib close to parity, and there is a higher relative risk for meloxicam and oral diclofenac. Diclofenac also has higher risk of liver toxicity, sulindac has less renal metabolism, meloxicam (at lower doses) has a favorable upper GI side-effect profile, and nabumetone is a pre-drug, which requires hepatic metabolism, but may reduce first pass upper GI toxicity. If a patient is on aspirin (ASA) prophylaxis, it is better to take ASA first to allow platelet binding, and then wait 1 hour to take the analgesic NSAID.
Other adverse effects with chronic NSAID use include renal carcinoma13,14 and atrial fibrillation.18 Topical NSAIDs, particularly diclofenac (patches, solutions, or gels), have been used for localized pain, and all topical agents have approximately 5% to 10% systemic absorption. There are now studies suggesting that chronic ASA use, and possibly other NSAIDs, may reduce the risk of GI (especially colon, esophagus, liver, and pancreas), skin, breast, ovarian, bladder, and prostate malignancies.19 There are antioxidant, anti-inflammatory supplements, or medical foods—including flavocoxib (Limbrel), which is FDA approved for the management of osteoarthritis—which may also be considered in patients in whom NSAIDs would otherwise be contraindicated.
Corticosteroids may reduce edema and inflammation, and stabilize nerve membranes. Corticosteroids possess analgesic properties for a variety of cancer pain syndromes, including bone pain and neuropathic pain from infiltration or compression of neural structures. They also alleviate nausea and increase mood and appetite, and may be used for symptoms associated with bowel obstruction.4 Acute use may result in peptic ulcers, psychosis, fluid retention, immunosuppression, and leukocytosis. Chronic use can increase risk of hyperglycemia, weight gain, osteoporosis, avascular necrosis, cataracts, myalgias and myopathy, and delayed wound healing. Therefore, corticosteroids that are required for more than 2 weeks duration should be used with caution, and should be tapered to reduce the risk of adrenal suppression.