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13 Articles in Volume 11, Issue #4
Diagnosing and Managing Hand Osteoarthritis
Difficult Migraine Patient
Electromagnetic Applications In Biology and Medicine
Excerpt from the Book Avoiding Opioid Abuse While Managing Pain
Hormone Therapies: Newest Advance in Pain Care
Make the Family Your Best Friend
Medications for Chronic Pain—Opioid Analgesics
Nonpharmacologic Remedies for Back Pain During Pregnancy
Reconsidering and Revising Evidence-Based Practice in Pain Medicine: Steps Toward Sustaining the Profession?
The Value of Blood Analysis for Compliance Monitoring
Treatment of Neuropathic Pain: The Role of Unique Opioid Agents
Understanding Potential Complications Of Epidural Steroid Injections
Unmasking Post-traumatic Headache

Medications for Chronic Pain—Opioid Analgesics

In part 2 of our 3-part series reviewing medications for the treatment of chronic pain, the author discusses specific guidelines for the use of opioid analgesics in cancer and chronic noncancer pain.

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 1. Select Practice Guidelines for Selection of Opioid Analgesics

Opioid Analgesics

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

Table 2. Oral/Transdermal Opioid Analgesics for Pain

Table 2. Oral/Transdermal Opioid Analgesics for Pain

Table 2. Oral/Transdermal Opioid Analgesics for Pain

Table 2. Oral/Transdermal Opioid Analgesics for Pain

Table 2. Oral/Transdermal Opioid Analgesics for Pain

Adverse Effects

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

No single method has been determined to be effective in identifying individuals at risk for opioid abuse.1 However, several tools are available for screening patients for the suitability of chronic opioid use and risk for abuse, such as the Screener and Opioid Assessment for Patients with Pain (SOAPP), the Opioid Risk Tool (ORT), and the Diagnosis, Intractability, Risk, Efficacy (DIRE) instrument. Patients should be assessed periodically, not only for pain relief, but also for any aberrant behavior and activity. Physical dependence should be evaluated when chronic opioid therapy is changed or discontinued. Abrupt discontinuation of an opioid after chronic use may precipitate withdrawal symptoms.10 Guidelines from the APS and the AAPM on chronic opioid use describe a range of dose-reduction methods, ranging from 10% per week to a more rapid 25% to 50% every few days, depending on the reason for discontinuation. Faster discontinuation rates may be associated with more withdrawal symptoms.3


The general dosing recommendations for opioid analgesics are given in Table 2.9-14 Unlike other analgesics, full agonist opioids have no true ceiling dose for pain relief.1,10 However, this is not true for partial agonists or mixed agonist/antagonist opioids, which do have a ceiling effect for their analgesic action. Dosing of opioid analgesics usually starts low and is titrated to achieve a balance of pain relief and tolerable side effects. If opioids combined with other analgesics (such as acetaminophen) are used, it may be necessary to change therapy to an opioid-only analgesic to avoid excessive dosing of the nonopioid component.

When using opioids for cancer and noncancer pain treatment, tolerance to the analgesic effects of the opioid may develop, requiring higher doses to achieve pain relief.7 This may result in intolerable side effects. Switching to a different opioid or rotating opioids has been shown to provide adequate analgesia and a decrease in side effects in patients not achieving pain relief with an initial opioid.7,8

Opioid equivalencies have been determined to aid in converting from one strong opioid to another or from a weak opioid to a strong opioid (see Table 3).2,10,14,19 It is important to note that these equivalent doses are estimates and dosing needs to be individualized, with titration based on response and tolerability. Converting from one opioid to another involves determining the 24-hour dosing requirement for the current opioid, calculating the equianalgesic total daily dose of the new opioid, and dividing by the number of doses per day for the new opioid.2 If pain was effectively controlled by the previous opioid, the dose of the new opioid should be reduced by 25% to 50% and the new opioid titrated during the first 24 hours to achieve pain relief. If pain was not controlled, the new opioid can be given at the equianalgesic dose. This conversion method does not apply to methadone. Because of methadone’s unique pharmacokinetics, the equianalgesic dose between methadone and other opioids varies considerably from patient to patient and with the dose of the opioid. It is generally recommended that methadone be used only by practitioners experienced with its use.

Table 3. Equianalgesic Doses of Opioid Analgesics

Risk Evaluation and Mitigation Strategies for Opioids

Patients treated with opioids for chronic pain need to be aware of the potential adverse effects and risks associated with their use. To ensure appropriate prescribing, dispensing, and use of opioids, the US Food and Drug Administration (FDA) has begun the process of developing standardized Risk Evaluation and Mitigation Strategies (REMS) for many drugs, including the opioid analgesics.21 These REMS include information that is specific for the patient, in the form of a medication guide, as well as information for the prescriber on appropriate use of opioid analgesics. One opioid analgesic—fentanyl transmucosal tablets (Abstral)—has been approved with a standardized REMS.22 Physicians, pharmacists, and other healthcare providers, as well as distributors, are required to enroll in the REMS program. Fentanyl buccal soluble film (Onsolis) has a required program called FOCUS for patients, physicians, pharmacists, and caregivers.23 A list of other opioids with some required REMS component can be found at the FDA REMS website.24

Counseling Pearls

For controlled- or extended-release formulations of opioids, patients should be cautioned not to break, crush, or chew tablets or capsules.9 Concurrent use of central nervous system depressants, such as alcohol, sedatives, and antihistamines, may increase the risk for sedation from opioids.10 Also, opioids may have sedative effects or may slow reflexes and coordination.2,3 Patients should be cautioned regarding these effects and their potential to interfere with driving or work activities. If fentanyl or buprenorphine transdermal patches are used, patients should be aware that the release of the drug from the transdermal system may be increased with exposure of the patch to heat, either external (eg, heat lamps or electric blankets) or internal (eg, exertion or fever) sources.2,10,14,19 To avoid inadvertent exposure to active drug after transdermal patch removal, patches should be folded for disposal, so the adhesive sides adhere to each other.19 Transdermal buprenorphine also comes with a special patch disposal unit that can be used to discard used patches.14


Opioid analgesics are effective therapy for patients with chronic pain that is not controlled by nonopioid analgesics. When dosed and titrated appropriately, opioid analgesics are generally well tolerated and safe. However, physicians, pharmacists, patients, and caregivers need to be aware of potentially serious adverse effects of opioids, differences in available formulations, and equianalgesic dosing.


Last updated on: September 6, 2011
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