A key benefit of using opioids to manage chronic pain is that they can be administered by a variety of routes. Compared with other analgesics, opioids are highly effective, easily titrated, and have a favorable benefit-to-risk ratio. According to cancer pain specialist Declan Walsh, "The single biggest problem in opioid drug therapy is underdosing."^[3]

The beneficial analgesic effect of opioids, their potential side effects, and the risks associated with their use can vary considerably among individuals.^[22] Some patients may not experience adequate pain control despite appropriate dose adjustments, whereas others may develop intolerable adverse effects to a particular opioid. These differences may be related to variance in genetic expression of opioid receptors, as well as to differences in the metabolism of these agents.^[23]

Opioid therapy must be individualized, such that each dose would provide a balance between effective analgesia and acceptable side effects. To achieve this goal, a gradual adjustment of the dose is usually required. Moreover, the appropriate agent that meets this goal may only be found through sequential trials of different opioids.^[24] As with the use of all medications, potential side effects should be discussed with the patient.

In terms of the sensitivity of pain types to opioids, visceral pain responds best, followed by somatic pain, and neuropathic pain. Neuropathic pain is relatively insensitive to opioids, and often necessitates the use of adjuvant analgesics, such as antiepileptics and older antidepressants, to obtain optimum pain control.^[3]

Normal pain sensation results from the activity of two neural systems working in tandem. Briefly, afferent peripheral nociceptors (nonmyelinated C fibers and myelinated A delta fibers), which carry pain signals, synapse with highly organized neurons in the dorsal horn of the spinal cord. The signals are then transmitted to the deep structures of the brain, specifically to the thalamus via the spinothalamic tract and to other, less well-described pathways. From there, the signals are passed to various areas of the cerebral cortex where they are processed. As these signals pass through the brainstem, they activate the antinociceptive system, an endogenous descending analgesic pathway, causing the release of endorphins from the periaqueductal gray matter as well as enkephalins from the nucleus raphe magnus. These endogenous opioids bind to and activate receptors on presynaptic and postsynaptic cells (mu receptors) and inhibitory interneurons (delta receptors), which, in turn, leads to a series of cellular events that prevent the transmission of pain signals.^[25]

Continual or repeated transmission of pain signals leads to the remodeling of pain pathways, making them hypersensitive to pain signals and resistant to antinociceptive input, and underlies the pathogenesis of chronic pain. These neural changes, known as neural plasticity, result in persistent pain often after healing is complete (or in the absence of disease), as well as the spread of pain to areas other than those involved with the initial injury or disease.^[1,4] Opioid analgesics mimic the effects of endorphins and enkephalins by blocking the repeated transmission of pain signals and the resulting remodeling by activation of the antinociceptive system.

Types of Opioids

Opioids are classified as pure agonists, partial agonists, or mixed agonist-antagonists, depending upon the specific receptors to which they bind and their specific activity at these receptors. Pure agonists are so named because they mimic the action of endogenous opioids most closely, and their effectiveness increases with increasing dose. Consequently, pure agonists such as morphine are the most commonly used opioids in the management of severe chronic cancer pain. Of note, these agents do not reverse or antagonize the effects of other pure agonists given simultaneously.

Partial agonists have less effect than do pure agonists at opioid receptors. Agents in this group include pentazocine, butorphanol, dezocine, and nalbuphine. Mixed agonist-antagonists, such as buprenorphine, block one type of opioid receptor while activating a different opioid receptor.^[10,13] The analgesic effectiveness of both partial agonists and mixed agonist-antagonists is limited by a dose-related ceiling effect. Consequently, these groups play a minor role in the management of cancer pain.

Long-acting opioids are typically recommended for the treatment of severe chronic cancer pain, and for select patients with chronic noncancer pain. Short-acting, or immediate-release, opioids are generally recommended when opioid therapy is being initiated for the first time or as rescue therapy for episodes of breakthrough pain. Once stable, patients can usually be switched to a controlled-release or slow-release formulation. Clinical experience suggests that selection of an effective pain regimen for the patient with chronic pain, combined with aggressive management of side effects, leads to improved overall functioning and quality of life (Table).

Table. Opioid Agonists Commonly Used in the Management of Chronic Pain

Agent	Formulations	Comments
Morphine	Several short- and long-acting formulations: injectable (IV, IM, SQ); immediate- and controlled-release (8-24 hours duration of action) tablets and suppositories; immediate-release syrup; controlled-release suspension	Standard of comparison for opioids
Hydromorphone	Several short- and long-acting formulations: injectable (IV, SQ); immediate- and controlled-release (with 8-12 hours duration of action) tablets or capsules; rectal; intraspinal	High bioavailability (78%) with SQ infusion
Oxymorphone	Short-acting formulation formulations: injectable (IV, IM, SQ) and rectal formulations
Codeine	Short- and long-acting formulations: immediate-release tablets (coformulated with NSAIDs); controlled-release single-agent tablets	Commonly used for mild to moderate pain
Dihydrocodeine	Short- and long-acting formulations: immediate-release tablets (coformulated with NSAIDs); controlled-release single-agent tablets
Oxycodone	Short- and long-acting formulations: immediate release tablets (coformulated with NSAIDs); controlled-release single-agent tablets and syrup	High bioavailability (60%) with oral formulation; single agent effective for severe pain
Hydrocodone	Short- and long-acting formulations: tablet, syrup, and sustained-release capsules (8-12 hours duration of action); coformulated with acetaminophen
Methadone	Oral and parenteral formulations	Used as a second- or third-line opioid for cancer pain; has a number of unique characteristics: excellent oral and rectal absorption, no known active metabolites, long plasma half-life (24 hours)
Levorphanol	Oral and parenteral formulations	Used as a second-line agent for chronic pain
Fentanyl	Short-acting, rapid-onset oral transmucosal formulation, optimal dose found by titration and not predicted by ATC dosing; long-acting transdermal patch provides 72 hours of stable drug delivery, 12-hour delay in onset and offset of action	Transdermal formulation: potency relative to other opioids not established
Tramadol	Long-acting formulation: controlled-release tablets	For mild to moderate pain; not a scheduled analgesic; weak opioid agonist; also inhibits reuptake of norepinephrine and serotonin

IV, intravenous; IM, intramuscular; SQ, subcutaneous; NSAIDs, nonsteroidal anti-inflammatory drugs; ATC, around-the-clock.
Adapted from: National Cancer Institute. Pain PDQ, Health Professional Version. Available at: http://www.nci.nih.gov/cancerinfo/pdq/supportivecare/ pain/healthprofessional/.
Accessed February 13, 2003. Cherny NI. The management of cancer pain. CA Cancer J Clin. 2000;50:70-116.

Routes of Opioid Administration

Opioids may be administered by several routes: oral, transmucosal, rectal, intravenous, subcutaneous, transdermal, and intraspinal (intrathecal and epidural). Individualized therapy should take into consideration several factors, including prior response to opioids and patient preference to route of administration. Initiating therapy with a short-acting oral agent is preferable, especially in the opioid-naive patient. Transitioning to a continuous-release agent, whether oral or transdermal, may easily be accomplished once tolerance to opioids is demonstrated.

Assessing the patient's response to several different oral opioids is recommended before switching to another route of administration. When changing drugs and not route of administration, comparisons must be made at equianalgesic doses. When changing route of administration and not drug, the dose of the drug must be adjusted; this is particularly important when switching between oral and parenteral routes if the opioid undergoes extensive first-pass metabolism.

Rectal administration is a safe, inexpensive, and effective route for delivery of opioids (and nonopioids) when a patient has nausea or vomiting or is otherwise unable to take medication by mouth or prefers another route. Transdermal (fentanyl) patches provide long-lasting analgesia (up to 72 hours) and typically are used for relatively stable analgesic requirements. Oral transmucosal fentanyl citrate (OTFC) is used for the relief of breakthrough pain primarily because of its rapid absorption and consequent rapid therapeutic effect (within 15 minutes).

Parenteral methods should be used only when simpler, less demanding, and less costly methods are inappropriate, ineffective, or unacceptable to the patient. This route may be useful if a patient cannot swallow and intravenous access is established. Intravenous administration provides a rapid onset of analgesia (within 2 to 10 minutes), but the duration of action may be shorter than with other routes. The subcutaneous route is as effective as the intravenous route, and may be more convenient in some situations, such as in home or hospice care. Because the bioavailability of opioids administered by a parenteral route (eg, morphine, hydromorphone, oxycodone, and codeine) is generally 2-3 times that of the oral route, when switching from the oral to the subcutaneous and intravenous routes, the dose must be decreased by one half or one third. Opioids administered parenterally may be given either intermittently (usually every 4 hours) or by continuous infusion.

In general, other routes of opioid administration are not recommended because they are either painful (ie, intramuscular) or are only useful in specific circumstances. For example, patient-controlled analgesia is used to determine an opioid dose when initiating therapy, and intraspinal administration of opioids (epidural or intrathecal) can be helpful in a very small select group of patients with intractable pain, such as those with bilateral or midline pain in the lower part of the body, or when systemic agents provoke intolerable side effects or inadequate pain relief.^[10]

Because chronic pain of both cancer and noncancer etiology share the same neural mechanisms, treatment approaches may be extrapolated from the management of chronic cancer pain to pain of other causes. Based on the findings of several studies and reports demonstrating analgesic efficacy and acceptable side effects with opioid therapy in a wide range of chronic painful conditions (eg, osteoarthritis, sickle cell anemia, back pain, phantom limb pain, neuropathic pain, and headache), many professional organizations as well as expert groups in pain management, including the American Pain Society, now support the judicious use of opioids for selected patients with chronic noncancer pain.

Side Effects of Opioids

The more common side effects of opioids include constipation, nausea, sedation, and cognitive impairment (ie, confusion and delirium). When the cause of specific side effects is thought to be due to the accumulation of active metabolites, a switch to another opioid may mitigate the side effects.^[10,13]

All patients on ATC opioid therapy need to be given laxatives prophylactically. Opioid-induced constipation is a frequent cause of chronic nausea and appears to be dose-related; it is characterized by large variability in individuals and is mediated by both central and peripheral mechanisms. Complete tolerance to this effect generally does not develop, and most patients require laxative/stool softener therapy for as long as they take opioids.^[10,13]

By contrast, although nausea and vomiting is a common side effect of exposure to opioids, tolerance tends to develop, such that the effect usually disappears within the first weeks of treatment. Prophylactic use of an antiemetic is not necessary routinely, but an appropriate antiemetic is usually effective in limiting nausea and vomiting and should be used during the initiation phase of opioid therapy. In some patients, nausea and vomiting may persist beyond the opioid-initiation phase or occur de novo in patients on long-term opioid treatment and may become chronic in nature.^[10,13]

Opioid-related central nervous system side effects include sedation, confusion and delirium, and myoclonus. Sedation and cognitive impairment commonly occur with the initiation of therapy or with dose escalation, but tolerance tends to develop to these effects, such that they usually disappear within the first week of treatment. In some patients, sedation and cognitive impairment may persist. Certain individuals may manifest a paradoxic stimulation with certain opioids, which may become attenuated with opioid rotation. Myoclonus, although common, is mild and infrequent; tolerance develops to this effect as well.^[10,13]