As discussed in part 1 of this two-part article, which began in the January issue of ONCOLOGY, distress caused by pain increases suffering further among elderly cancer patients and their primary caregivers, especially when these symptoms are not recognized and treated appropriately. In part 1, we addressed the pathophysiology of pain, how aging affects the perception of pain, and the multidisciplinary evaluation of pain in this population. Part 2 will deal with pharmacologic approaches to treating pain, including opioid and nonopioid analgesics, as well as nonpharmacologic options.
Cancer pain can be controlled with simple treatments in more than 80% of cases. In the other 20%, a multidisciplinary approach with careful reassessment of the pain syndrome and use of adjuvant medications and/or nonpharmacologic interventions is needed to control pain.[1] Oral analgesics are the most common treatment of cancer pain. The World Health Organization (WHO) pain ladder, a widely used algorithm in pain management, classifies these agents as (1) nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (paracetamol); and (2) opioids.[1-3]
Pharmacologic Management
Nonopioid Analgesics
The NSAIDs are a group of medications used for their anti-inflammatory properties and to decrease fever and pain. They can be used in combination with opioids. They act in the periphery, decreasing prostaglandin synthesis, and thus reduce the activity of the N-methyl-d-aspartate (NMDA) receptor in the central nervous system.[3] The NSAIDs also can be partially active at the central level via dorsal horn expression of cyclo-oxygenase (COX)-1 and (COX)-2.[2-6] NSAIDs can be beneficial in the treatment of inflammatory pain, such as that produced by bone metastases. Their activity has a ceiling effect, however, in that increments in the dose over a certain level will result in no further improvement of analgesia.[2,3]
NSAIDs can cause several side effects that might limit their use in older cancer patients, such as renal toxicity, gastrointestinal bleeding and ulceration, and inhibition of platelet aggregation. A proton-pump inhibitor can be recommended to decrease the incidence of gastric ulceration secondary to NSAIDs, but there is no protection against renal toxicity.
Acetaminophen does not have anti-inflammatory properties, but it has antipyretic and analgesic properties and can be combined with opioids.[3] It is well tolerated and not habit forming, and its elimination is not affected by aging. Total dose should not exceed 4 g/d, because in larger doses it can damage the kidneys and liver.[2,3,5]
Opioid Analgesics
Because elderly cancer patients are more likely to be affected by the acute and chronic toxicities of opioids, opioids should be initially administered at a lower dose and titrated cautiously.[7]
Over 20 different opioids are used in clinical practice. They can be classified as natural opioids (eg, codeine, morphine), semisynthetic opioids (eg, buprenorphine, diamorphine [the British approved name for legally prescribed heroin]), or synthetic opioids (eg, meperidine [pethidine], methadone)[2,4-6]; they also can be categorized as weak (to treat mild to moderate pain) or strong (to treat severe pain).[1,3]
Opioids mimic the action of the endogenous opioid peptides at opioid receptors. They can suppress the activation of voltage-dependent calcium channels presynaptically and postsynaptically or activate potassium channels postsynaptically. This suppression results in decreased excitability and suppression of activity-dependent transmitter release from the neurons or by the action of adenylylcyclase, thereby decreasing impulses to the brain and spinal cord.[2,8] Opioids also indirectly produce analgesia by modulating noxious stimuli through the descending inhibitory pathway.[2,9]
Opioid receptors are glycoproteins that exist in many organ systems, such as the lungs, cardiovascular system, gastrointestinal tract, and bladder.[9] The four major receptor types are the mu-opioid receptor (MOP), delta-opioid receptor (DOP), kappa-opioid receptor (KOP), and nociceptin peptide factor (NOP). Most of the opioids used clinically are selective for MOP, although they might interact with the other receptor subtypes if administered in high doses. Evidence from human and animal studies indicates that there are at least seven different variants of mu-receptors,[10] suggesting that incomplete tolerance simply reflects the difference in drug selectivity among those receptors.[2,10]
Opioid tolerance is defined as a decrease in opioid effect, manifested as a patient requiring an increasing dose of an analgesic to maintain its therapeutic effect. The NMDA receptor plays a central role in the mechanism of tolerance. Antagonism of the NMDA receptor yields better pain control, as seen with the administration of methadone, a competitive antagonist of the NMDA receptor.[2] Opioids have no maximum doses; they can be titrated until pain is relieved or adverse effects occur.[3] Addiction to opioids is extremely rare in elderly persons.[3,5]
• Weak Opioids—Weak opioids such as tramadol and codeine may have limited efficacy in cancer pain. Most of the analgesic effect offered by codeine is through its conversion to morphine in the central nervous system, although the morphine yield is relatively small.[3] The morphine is then converted to metabolites, which can accumulate in the presence of renal failure. Codeine undergoes filtration at the glomerulus, tubular secretion, and passive reabsorption.[3] Tramadol inhibits monoamine uptake. It is highly metabolized in the liver to one active metabolite, O-demethyl tramadol, and 90% is excreted by the kidneys. The pharmacokinetic properties of the drug do not change in elderly persons.[3,5] Another weak opioid, dextropropoxyphene, is metabolized in the liver to norpropoxyphene and excreted by the kidney. The metabolite can accumulate in patients with renal impairment; it has a long half-life and can cause toxicity.[3]
