Medications for Chronic Pain—Opioid Analgesics
Chronic pain is associated with significant health and economic costs on both the individual and societal levels.1 Estimates of the prevalence of chronic pain vary and range from 2% to as high as 40%. Causes of chronic pain also vary and include fibromyalgia, neck or low back disorders, arthritis, neuropathies, and cancer.1-3 Various treatments are available for chronic pain, including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, and other treatments such as anticonvulsants and antidepressants. This second article in a 3-part series on medications for chronic pain will discuss opioid analgesics.
Therapeutic Role of Opioid Analgesics
As with other analgesics, opioids can be used to treat many types of chronic pain, including pain associated with cancer as well as noncancer conditions. Studies have shown opioids to be effective in providing relief of chronic pain, with efficacy that is greater than that of placebo but comparable to that of nonopioid analgesics in some situations.4-8
Several professional organizations, including the American Society of Interventional Pain Physicians (ASIPP), the American Pain Society (APS), the American Academy of Pain Medicine (AAPM), and the National Comprehensive Cancer Network (NCCN), have developed guidelines on the use of opioid analgesics for the treatment of cancer and chronic noncancer pain. These guidelines are summarized in Table 1.1-3 For cancer pain, the selection of an analgesic is based on pain severity.2 Guidelines on the use of opioids for chronic noncancer pain stress the importance of patient evaluation and selection before initiation of opioids to determine the suitability of opioid analgesics.1,3 When needed, opioid analgesics are initiated with short-acting formulations until pain control is achieved. Long-acting formulations then can be used, with short-acting agents given for breakthrough pain.2
Table 2 lists the available oral and topical opioid analgesics.9-14 Opioids exert their analgesic effect by acting as agonists at the opioid receptors—primarily the mu receptor.15,16 Most opioids exhibit selectivity for this opioid receptor. However, as the dose increases, selectivity can be lost and other opioid receptors (eg, kappa and delta receptors) can be affected, increasing certain side effects of opioids such as sedation, respiratory depression, and euphoria.
Opioid analgesics can be classified by chemical structure (phenanthrenes, phenylpiperidines, or diphenylheptanes) and by the degree of agonist action at the receptor site (see Table 2).6,9,10 Fentanyl, hydromorphone, levorphanol, meperidine, morphine, oxycodone, and oxymorphone are considered strong full agonists or strong opioids. Codeine, hydrocodone, tapentadol, and tramadol are considered weak full agonist opioids. Both tramadol and tapentadol have additional mechanisms of action—norepinephrine and serotonin reuptake inhibition for tramadol and norepinephrine reuptake inhibition for tapentadol. Overall, weak full agonist opioids have not been shown to be more effective for pain relief than nonopioid analgesics such as NSAIDs or antidepressants. Therefore, these agents are frequently combined with other analgesics, such as acetaminophen, to enhance efficacy.6,10
In addition to full agonist activity at the opioid receptor, some opioids are partial agonists or have mixed agonist/antagonist activity (see Table 2).1,10,16 Partial agonists have a high affinity for the opioid receptor but have a weaker pharmacologic effect.17 Opioid antagonists can reverse the opioid effect at the receptor and have the potential to precipitate withdrawal symptoms in patients dependent on full agonist opioids.10,16 The use of mixed agonist/antagonist opioids in chronic cancer pain is not recommended, and current guidelines do not specifically address the use of partial agonists or mixed agonists/antagonists for chronic noncancer pain.1-3
When titrated appropriately, opioid analgesics generally are well tolerated. However, when high doses are needed, adverse effects may become intolerable for some patients. Compared with placebo, opioid analgesics have been associated with higher rates of constipation, nausea, dizziness, drowsiness/sedation, vomiting, and itching.4,6 Some of these effects, such as drowsiness, vomiting, and nausea, may resolve with continued therapy.2 Others, such as constipation or itching, may require preventive measures to avoid further complications. Stool softeners (eg, docusate or polyethylene glycol), fluids, dietary fiber, and exercise are recommended to prevent opioid-induced constipation. If constipation occurs and persists, magnesium hydroxide, bisacodyl, lactulose, or saline/tap water enemas may be needed to avoid impaction. Antihistamines may be effective for itching, although their combined use with opioids may increase sedation.
One serious, potentially life-threatening adverse effect of opioids is respiratory depression.2,10 Opioid-naïve patients, those with preexisting respiratory disorders, and the elderly may be especially at risk for this complication. The risk for respiratory depression may be higher with methadone.18 This effect may occur later than the analgesic effect of methadone, and inappropriate titration may result in an overdose of the drug and subsequent respiratory depression. Also, patients tolerant to high doses of other opioids may not be tolerant to methadone; therefore, conversion from high doses of other opioids to methadone must be done cautiously. The risk for respiratory depression also can be increased when fentanyl is used with other drugs that interfere with its metabolism (eg, cytochrome P4503A4 inhibitors) because of an increase in its plasma concentrations.19 Opioid abuse or misuse also can contribute to the risk for respiratory depression.
Chronic use of opioids for noncancer pain may be associated with a risk for opioid abuse.1 With chronic opioid use, rates of abuse have been reported to range from 18% to 41%. This risk, however, may be lower with partial agonists or mixed agonist/antagonist opioids.10 Several factors or characteristics associated with an increased risk for opioid abuse have been identified, including younger age, multiple healthcare visits (>20 per year), a history of nonopioid substance abuse, a mental health diagnosis, receiving more than 210 days’ supply of opioids; marital status (separated, divorced, or single), and African-American race.20