Acetaminophen (paracetamol) is a commonly used analgesic that has little clinical anti-inflammatory activity. It is used as initial therapy for mild pain and as a continued medication for cancer pain management in the elderly. Step 2 of the WHO pain ladder has classically included acetaminophen/opioid combination products (Table 4.1). Many clinicians stop acetaminophen once they have moved to step 3 of the WHO ladder. A recent randomized controlled trial (RCT) in patients with cancer has shown that the addition of acetaminophen to opioids used in the treatment of severe pain results in added analgesic effect (2). Safety concerns about the effects of high and continued dosing of acetaminophen on the kidney and liver are well established (3). The current recommendation for maximum dosage of acetaminophen is 4 g per day. As with other analgesic regimens in palliative care, scheduled acetaminophen is usually the most appropriate (Table 4.2).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are traditional step 1 opioids of the WHO ladder. They are effective in the treatment of mild pain, and have an opioid-sparing effect for moderate to severe pain (4). Many NSAIDs in the United States have both prescription and nonprescription formulations; these are generally equally effective when equivalent doses are given.

NSAIDs are effective through the inhibition of the enzyme cyclo-oxygenase, resulting in the reduction of prostaglandin synthesis. Cyclo-oxygenase has two isoforms: the constitutive variety known as cyclo-oxygenase-1 (COX-1) and an inducible variety known as cyclo-oxygenase-2 (COX-2). COX-1 is involved in the normal physiology of the stomach, kidney, and other organs, and platelets. In the stomach, COX-1 participates in the production of prostaglandins that generate the protective barrier of the gastric mucosa and modulates the extent of gastric acid production. COX-2 is found primarily in the brain and kidney, is produced elsewhere in the body in response to pain and inflammation, and is a key element in the inflammatory cascade. The preferential inhibition of COX-2 leads to a relatively improved toxicity profile without loss of anti-inflammatory or analgesic effects. COX-2 inhibitors have a relatively reduced risk of gastrointestinal toxicity and no effect on platelet function. COX-2 inhibitors have continued renal toxicity and a risk of myocardial infarction. It is debatable whether this is a class effect or directly associated with individual drugs.

NSAID gastropathy and nephropathy can be minimized by using these medications carefully in patients with increased risk of gastrointestinal and renal disorders. Good hydration is essential to minimize adverse renal effects. The risk of renal dysfunction is greatest in patients with preexisting renal impairment, heart failure, hepatic dysfunction, hypovolemia, and concomitant therapy with other nephrotoxic drugs such as diuretics, cisplatin, aminoglycosides, and amphotericin B. Older patients with intrinsic renal disease are at increased risk of adverse renal effects from NSAIDs. In addition, the antipyretic and anti-inflammatory effects of NSAIDs may mask the usual signs and symptoms of infection, which may be particularly important in patients with neutropenia.

NSAIDs are effective in the treatment of mild cancer pain and also have an opioid-sparing effect for moderate to severe pain. They may be most useful in the treatment of cancer-related pain when it is associated with inflammation: for example, in patients with pain from bone metastasis. Although, a dose–response relationship exists with both nonselective and COX-2–selective NSAIDs, each individual drug has a maximum therapeutic dose above which there is no additional analgesic effect, but there is an increased risk of toxicity with further dose escalation (ceiling effect). Mercandante et al. (4) confirmed the opioid-sparing nature of NSAIDs. The addition of ketorolac, 60 mg daily, resulted in a significant reduction in opioid dosing. Patients receiving ketorolac had less constipation but more gastric discomfort. This positive effect may be related to the significant potency of ketorolac, which has a limited duration of prescribing (5 days) because of its nephrotoxicity. It is commonly used in both peri- and postoperative analgesia but may be associated with an increased risk of bleeding. A recent Cochrane review of the effects of NSAIDs, alone or combined with opioids, for the treatment of cancer pain showed that NSAIDs had a clear benefit over placebo. There were differences in side effects, while some studies showed improved efficacy of some NSAIDs over others. In terms of the combined therapy of opioids and NSAIDs, there was a statistical advantage for the combination in 9 of 23 studies. Most of the studies were of <7 days’ duration, making their applicability to the general cancer population questionable. Most clinicians continue to recommend NSAIDs especially for patients with bone pain. The potential cardiac toxicity of COX-2–selective NSAIDs is not likely to be a factor in the treatment of cancer pain in the palliative care setting, but should be discussed with the patient.

Although corticosteroids were not developed for the primary purpose of analgesia, they effectively act with the same mechanism as NSAIDs, decreasing the inflammatory cell response (steroidal anti-inflammatory drugs). In cancer practice, steroids have been used in the treatment of depressed appetite, malignant bowel obstruction, and nausea, and to improve the quality of life generally. Apart from the pain of bowel obstruction, other pain syndromes that are improved with the use of steroids include bone pain, liver capsule pain, and headache from increased intracranial pressure caused by brain metastases. Steroids can reduce the neurologic impact and pain of malignant spinal cord compression, and a response to steroids is in fact a prognostic sign for response to radiotherapy. The reduction of edema around nerves may be an important mechanism in their role in neuropathic pain.

Few studies have formally assessed the effect of corticosteroids on pain; however, studies in hormone-refractory metastatic prostate cancer give some guidance (5). In this study, patients were randomized to receive mitoxantrone and prednisone versus prednisone alone (10 mg daily). Ten of 81 patients (12%) treated with prednisone alone had a reduction in pain compared with 23 of 80 (29%) of those who received mitoxantrone and prednisone. A further seven had no reduction in pain but a >50% reduction in pain medicines. The median duration of pain response, defined as a two-point decrease in pain on a six-point scale without an increase in analgesic medications, was 18 weeks in the prednisone alone arm. Many of these patients had bone disease, suggesting an anti-inflammatory effect of steroids.

Corticosteroids are not without side effects. In the short term, one must be conscious of the potential for fluid retention, hyperglycemia, gastric irritation, and oral candidiasis. When given for a prolonged period, steroids may cause a proximal myopathy immunosuppression leading to opportunistic infections, cushingoid habitus, and some neuropsychiatric syndromes including delirium, especially in the elderly. A mild dysphoria may actually be a positive effect of steroids. Patients administered steroids for more than a few days should be given some form of gastric mucosal protection (e.g., H₂ receptor antagonists, proton pump inhibitors) and an antifungal mouthwash for the prevention of oral thrush. When higher doses are used for more than a few weeks, the addition of prophylaxis for Pneumocystis [e.g., trimethoprim/sulfamethoxazole (Bactrim)] may be considered.

Anticonvulsants (Table 4.3) have become commonly used for the treatment of cancer pain, with little evidence of their overall effect (6). In a Cochrane Systematic review, 23 studies were considered for analgesic effectiveness (7). In these studies, which each involved >1000 patients with largely nonmalignant conditions, the primary measure used was the number-needed-to-treat (NNT), allowing better comparison of the effectiveness. NNT is the number of patients required to treat to achieve a >50% reduction in pain intensity in one patient (Table 4.4). Carbamazepine, phenytoin, and gabapentin have been shown to have some analgesic efficacy. A single study with sodium valproate showed no analgesic effect. Newer anticonvulsant medications have also been studied.

Gabapentin has found many uses within medicine, often without clear evidence of effectiveness. Its role in the treatment of cancer-related neuropathic pain has now been confirmed in clinical trials. RCTs with placebo have demonstrated the efficacy and tolerability of gabapentin for the treatment of postherpetic neuralgia (PHN) (8, 9) and painful diabetic neuropathy (10). For PHN, the NNT is 3.2 (CI 2.4–5.0), while for diabetic neuropathy the NNT is 3.8 (CI 2.4–8.7) (Table 4.4). Two small open-label studies (11, 12) have suggested that gabapentin may be effective in the management of neuropathic pain associated with cancer and cancer treatment. A systemic review showed that these smaller nonrandomized studies supported the randomized controlled studies (13). In a later randomized controlled study, the addition of gabapentin showed an improvement in analgesia in patients already receiving opioids for cancer pain (14). Patients with dysesthesia were more likely to be responsive to gabapentin. The qualities of pain often alleviated by gabapentin, include lancinating, burning, and aching pain, as well as allodynia, confirming the need for a careful and ongoing assessment. In a retrospective review of insurance claim data, the addition of gabapentin to morphine in the treatment of PHN resulted in a reduction in the required morphine dose (15). Gabapentin is well tolerated, with most patients experiencing few intolerable side effects. Treatment is usually started at 100–300 mg per day, with evening dosing often assisting with sleep. The most common side effects are sedation and dizziness with nausea, and confusion, with lower extremity edema occurring infrequently. Although studies and clinical experience have suggested that the effective dosage appears to be in the order of 2700 mg per day, RCTs have not established a clear benefit with dosages >1800 mg per day (administered in three divided doses), but individual dose titration is important. Doses should be reduced in patients with renal insufficiency.

Other anticonvulsants have been and continue to be used in the treatment of neuropathic pain. Carbamazepine is commonly used in the treatment of trigeminal neuralgia. The Cochrane review included three placebo-controlled trials of carbamazepine in patients with trigeminal neuralgia. The review showed an NNT of 2.5 (CI 2.0–3.4) patients to achieve a response in a single patient. Although small controlled trials have demonstrated the efficacy of carbamazepine for painful diabetic neuropathy (NNT = 2.3) (Table 4.4), there is little evidence to support its role in cancer neuropathic pain, with only one study in this population. It may be a difficult drug to use in patients receiving chemotherapy because it is contraindicated in patients with leukocyte counts <4000 per μL or absolute neutrophil count of <1500 per μL. Regular complete blood counts (CBC) are usually recommended, creating considerable burden in the palliative care setting. When studies of the
different conditions were combined, carbamazepine was found to have increased side effects compared with other anticonvulsants. Oxcarbazepine is a derivative of carbamazepine that has been shown to have analgesic activity in painful diabetic neuropathy (16). Small controlled trials have demonstrated the efficacy of phenytoin for painful diabetic neuropathy (7). Although serum concentrations can be monitored, its poor efficacy and high incidence of intolerable side effects (e.g., confusion, ataxia, nystagmus, nausea) outweighs this potential advantage and has resulted in its minimal clinical use. Loading doses may result in a rapid response to pain, but its nonlinear kinetics makes it a difficult drug to titrate.