Chapter 58. Opioid Pharmacotherapy

Among the remedies which it has pleased almighty God to give to man to relieve his sufferings, none is so universal and efficacious as opium.

Sir Thomas Sydenham, 1680

Opium is a heterogeneous drug derived from the milky exudate of the opium poppy, Papaver somniferum. The word opium is derived from the Greek word for juice. This natural product, which contains over 20 different alkaloids, has been used to control human discomfort for over five millennia. Opium was used clinically in the early days of European medicine, but it fell into disfavor because of toxic outcomes from nonstandardized drugs that were not used with necessary care. Paracelsus repopularized the use of opium in the 16th century, and by the second half of that century, clinical use of opium was understood and adopted by physicians throughout the continent.

The French pharmacist Jean-François Derosne isolated a crystalline precipitate from opium in 1803, but that material was a mixture of morphine and narcotine. It was not until 3 years later that the German pharmacist Friedrich Wilhelm Sertürner isolated the alkaloid morphine from opium. He named this powerful drug after Morpheus, the Greek god of dreams. Other opium alkaloids including papaverine and codeine were soon isolated, and within a few decades, the purified alkaloids began to replace crude opium in clinical practice.

Narcotic—a term derived from the Greek word meaning benumbing—was originally used to describe opium derivatives. Today, narcotic has become a legal term that includes a broad range of sedating and potentially abused drugs, many of which are not at all related to opium. Because the word narcotic has such negative connotations, clinicians should not use it when talking with patients. Opioid is the preferred term in both clinical and scientific dialogue. Opioids are literally opium-like substances. In the recent past, opioid was used primarily to describe endogenous opium-like substances, and the term opiate was used to describe drugs that are opium derivatives. The differences between exogenous opioids, such as morphine, and endogenous opioids, such as β-endorphin, do not justify differing terminology. Opioid accurately describes both types of compounds and is generally considered the preferred term today.

It is not logical that the human body should contain specific receptors for alkaloids derived from a plant. The presence of endogenous opioids was postulated to explain the presence of opioid receptors before the endogenous substances were isolated. Three distinct families of endogenous human opioid peptides, the endorphins, enkephalins, and dynorphins, have been isolated. These peptides are found within the central nervous system (CNS), adrenal medulla, nerve plexi, gastric exocrine glands, and intestines. These peptides appear to have multiple roles including modulation of pain, neurohumoral transmission, and neurohormonal effects.

Opioids remain the most effective analgesics available. They are clinically useful in treating diarrhea and gastrointestinal hypermotility because activation of opioid receptors in the intestines slows peristalsis. Opioids decrease respiratory activity that can be useful in anesthetized patients and to help manage air hunger, especially at end of life. They also have an impact on psychological state by lessening anxiety and excitation, and induce a feeling of well-being.

Much of the opioid pharmacology learned by health care professional students is based on studies conducted in lower animals or isolated tissues. Rarely do such studies suggest or consider the profound cognitive effects of pain and analgesia that greatly influence outcomes of opioid therapy in humans. Serious opioid misunderstanding among health care providers results from failure to recognize the great differences between potential acute opioid toxicity and that seen with long-term therapy. Incorrect assumptions and beliefs about opioid toxicity, addiction potential, and tolerance to analgesic effects have led to poor use of these effective drugs in many clinical settings. This has lead to widespread opiophobia, which has been defined as the irrational and undocumented fear that appropriate use of opioids causes addiction.1

In the middle of the 19th century, many of the patent medicines sold as panaceas or cure-alls contained opioids. Steadily increasing federal and state control of opioids in the United States began with the passage of the Harrison Narcotic Act in 1914. The federal Bureau of Narcotics was created in the 20th century to address use of potentially abused drugs. In recent decades, political and law enforcement demands, rather than scientific or clinical findings, have defined the control system for opioid use in the United States. Creation of the Drug Enforcement Administration (DEA) by the Controlled Substance Act of 1970 assured that control of opioids and other controlled substances would be driven by a law enforcement, not a patient care focus. Numerous initiatives, both within and outside of the government, have worked to emphasize that opioids are important—and frequently underused—clinical drugs. These include the 1979 Report to the White House of the federal Interagency Committee on New Therapies for Pain and Discomfort,2 the 1985 report of the federal Interagency Committee on Pain and Analgesia,3 and the 1986 National Institutes of Health Consensus Development Conference Report entitled “The Integrated Approach to the Management of Pain.”4

When Congress created the Agency for Health Care Policy and Research (AHCPR) of the Public Health Service in 1989, the agency was explicitly charged to develop clinical practice guidelines for areas of health care that were delivered inconsistently. Pain was selected as the first topic to be addressed. This is reflective of the serious concerns that the American public and public health professionals had about the ways in which pain management often was provided. Two federal clinical practice guidelines resulted. Acute Pain Management was published in 1992.5Cancer Pain Management was published in 1994.6 The full text for both these guidelines is available in a searchable format on the World Wide Web at www.ahrq.gov. These scientifically based references document serious misconceptions about use and underuse of opioids in the management of both acute and chronic malignant pain.

The use of opioids in chronic nonmalignant pain was considered controversial by many clinicians well into the 1990s. This controversy existed despite numerous published studies that documented the safety and efficacy of opioids in the management of a variety of chronic nonmalignant pain states, that is, neuropathic, myofascial, arthritic, and osteoporosis pain.7

In 1997, the American Academy of Pain Medicine and the American Pain Society published a joint consensus statement entitled, “The Use of Opioids for the Treatment of Chronic Pain.”8 A year later, the Federation of State Medical Boards of the United States published “Model Guidelines for the Use of Controlled Substances in the Treatment of Pain.”9 These two authoritative publications clearly document that opioids have a place in the management of many patients’ chronic nonmalignant pain.

Most physicians are far more willing to use opioid analgesics in patients with cancer than noncancer pain. The fact that opioids are seriously underused was underscored by a study of opioid prescribing for cancer pain patients that was published in the Journal of the American Medical Association in 1998.10 Researchers evaluated the records of 13,625 cancer patients discharged from hospitals to Medicare or Medicaid certified nursing homes during the 4-year period 1992 to 1995 in five states. A total of 4003 patients reported and had multiple factors independently associated with daily pain. Only 26% of these patients received morphine or another opioid considered to be on level 3 of the World Health Organization (WHO) analgesic ladder 11 (Fig. 58-1). Only 32 % of the patients received a step 2 analgesic, and 26% received only acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) for analgesia.

The WHO analgesic ladder that was developed to guide analgesic therapy for cancer patients in developing countries has been shown to be applicable in most pain management in most societies (WHO 1986). This approach describes three levels of analgesia. It suggests that pharmacologic management of mild to moderate pain should include a NSAID or acetaminophen unless there is a contraindication as a first step. When pain persists or increases, add an opioid for the second step. The third step consists of increasing the opioid dose to treat persistent moderate to severe pain. This is not a stepped approach in which prior steps must be tried before initiating more aggressive therapy. Analgesia should be started at the level appropriate for the patient’s pain. For cancer pain, a fourth step including palliative radiation and chemotherapy, nerve blocks, and various other modalities exists in developed countries

Morphine remains the standard for opioid comparisons. Most equianalgesic dose tables use parenteral morphine 10 mg every 4 hours as the standard for comparison. Equianalgesic doses are listed in Table 58-1. No such table will always apply for all patients due to great interpatient variances in response to opioids. The tables do provide an approximation of equally effective doses, but patients must often be re-titrated to response when the opioids they are taking are changed. It is important to differentiate among the pure mu (μ)-opioid receptor agonists, mixed agonist-antagonists (which are kappa (κ)-opioid receptor agonists and either antagonistic or neutral at μ receptors), and partial agonists. There is no proven difference in analgesic activity among the pure μ agonists. Greater potency does not imply higher activity. Potency differences simply mean that different amounts of drug must be used to obtain the same activity. However, pharmacokinetic differences can be clinically important. Pharmacokinetic parameters to consider include the peak serum level (Cmax), time to peak serum level (Tmax), and elimination half-life (T1/2). Oral-to-parenteral dose ratios also vary among opioids. And differences in metabolism (biotransformation) may sometimes make one opioid preferable to another, especially in a patient with impaired metabolism or elimination. Opioids may be long acting due to inherent pharmacologic factors, for example, methadone, levorphanol, or pharmaceutical formulation. Each type has advantages and disadvantages.

Opioids can be administered by a number of routes, including oral, parenteral, rectal, sublingual, transdermal, and transmucosal. Currently, three general types of opioids are available for clinical use. These include μ agonists, mixed agonist/antagonists (i.e., κ agonists), and partial μ agonists. As discussed later, κ agonists and partial μ agonists exhibit a dose ceiling effect that limits their clinical utility (See section, Opioid Mechanism of Action). The reader is referred to Table 58-2 for a list of commercially available μ-agonist opioids.

The μ agonists can be placed into three categories on the basis of their pharmacokinetic parameters (See section, Pharmacokinetics): short-acting, long-acting, and ultrashort-acting. The prototype opioid, morphine, represents the most commonly utilized type of opioid. Morphine and other opioids with short half-lives require frequent administration to maintain analgesia. Immediate-release morphine products provide about 4 hours of pain relief, and need to be dosed accordingly. Controlled-release formulations (MS Contin, Oramorph-SR, Kadian, Avinza, and OxyContin orally and Duragesic transdermally) provide alternatives to frequent opioid administration. Medications with longer half-lives, for example, methadone and levorphanol, yield analgesia for 6 to 12 hours. These medications are more expensive than controlled-release products.

The fentanyl series of μ agonists are highly lipophilic, which allows them to be utilized differently from the other μ agonists. They have rapid onset of action, which facilitates use as a preoperative adjunct. The high lipophilicity facilitates transdermal and subcutaneous administration. When administered through or under the skin, these medications depot in subcutaneous fat. Medication is released from the fat slowly. Conversely, when these medications are administered transmucosally or sublingually, they are rapidly absorbed due to the lack of the buccal and sublingual fat. Rapid absorption following transmucosal and sublingual administration makes these drugs useful in managing breakthrough pain.

Opioid receptors are found in the central nervous system and gastrointestinal tract and, to a lesser degree, in peripheral tissues. Opioid drugs manifest analgesic effects primarily by binding to and activating (agonizing) opioid receptors in the central nervous system (CNS). The interaction of exogenous opioids, for example, morphine and opioid receptors, mimics the interaction seen when endogenous opioid peptides (dynorphins, endorphins, enkephalins) bind with these same receptors.12

The three generally recognized classes of opioid receptors are the mu (μ), delta (δ), and kappa (κ) receptors.13–15 Sigma (σ) and epsilon (ε) receptors were formerly classified as opioid receptors because opioids can bind to them. However, neither is currently considered to be an opioid receptor per se, because activation does not necessarily result in analgesia and neither of these receptor types is opioid-specific.16

Opioid receptors are composed of glycoproteins found in cellular membranes. These receptors are coupled to G proteins that modulate potassium and calcium ion conduction17 (Fig. 58-2). When opioid agonists occupy either μ- or δ-opioid receptors, they open a potassium ion channel that permits an increase in potassium conductance. The hyperpolarization inhibits neuronal activity. In contrast, κ-receptor activation inhibits calcium entry via a calcium ion channel. Activation of the opioid receptors decreases transmission of signals from the primary peripheral afferent nerves to higher CNS centers, as well as the processing of the pain stimulus.18

Activation of the opioid receptors leads to analgesia as well as adverse effects. All three opioid receptor types have known subtypes (Table 58-3). Two μ subtypes have been best elucidated. Activation of μ1 leads to supraspinal analgesia, whereas μ2 activation is commonly thought to be responsible for the adverse sequelae of opioid administration. Activation of κ and δ receptors leads to spinal analgesia. However, κ3 receptors are thought to mediate supraspinal analgesia.19 Activation of δ receptors may actually potentiate μ-receptor-induced analgesia. Clinical implications of the δ- and κ-receptor subtypes have not been fully developed at this time.

Recently, the role of peripheral opioid receptors has been described. It is now thought that μ and κ receptors found in peripheral tissues can effect inflammation and exert antihyperalgesic activity.15 Opioids administered topically or by intraarticular injection have been used to treat pain in soft tissue and joints.20–22 The clinical significance of the peripheral effects of opioids is currently under debate.18

The lock-and-key receptor theory best describes the interaction of receptors and opioids23 (Fig. 58-3). Opioids can be full or partial agonists. Partial agonists occupy part of an opioid receptor, resulting in a lesser degree of analgesia than a full agonist. Antagonists can prevent opioid agonists from occupying opioid receptors. Clinically useful antagonists bind to the receptors rapidly and have a higher affinity for the receptors than agonists. Any agonist with a higher affinity for the receptor than one that is already on the receptor may displace the drug with lower affinity. If the second agent (agent with higher affinity) provides less activity than the drug administered previously, withdrawal may occur. Antagonism due to direct receptor binding is competitive, whereas agents that bind near opioid receptors can produce noncompetitive antagonism. Mixed agonist-antagonist opioids are agonists at κ receptors and block μ receptors.

The presence of a dose ceiling effect limits the usefulness of κ agonists and partial agonists as well as codeine as a result of different types of dose ceiling effects. A true dose ceiling is due to lack of additional efficacy after the dose exceeds a predetermined level while incurring additional adverse effects. Both mixed agonist-antagonist opioids (butorphanol, nalbuphine, pentazocine) and the partial agonist (buprenorphine) have true dose ceilings. Therefore, these drugs should not be administered at doses that exceed those listed in the FDA-approved labeling. These analgesics can displace pure μ agonists from μ-receptor sites, resulting in withdrawal. The second type of dose ceiling, which occurs with codeine, is due to unacceptable side effects, that is, nausea and constipation.24 The oral dose of codeine administered every 4 hours normally should not exceed 65 to 100 mg. Higher doses produce far more incremental side effects than incremental analgesia. Pure μ-opioid agonists (e.g., morphine) do not exhibit a true dose ceiling effect; however, they can present a functional ceiling that varies broadly among patients. For most patients, the functional ceiling is higher than doses needed clinically. The dose or serum concentration at which this functional ceiling occurs cannot be predicted a priori. Therefore, the dose of these drugs should be titrated upward until either analgesia or unacceptable side effects occur (See section, Dosing).

Pharmacokinetic factors impact the effectiveness of any given route of administration. Commonly, four phases of pharmacokinetics are considered: absorption, distribution, metabolism, and elimination. The availability of pharmaceutically formulated controlled-release dosage forms adds another dimension for consideration.

Absorption

Morphine and other opioids are readily absorbed from the GI tract following oral or rectal administration. Oral administration is convenient, simple, and inexpensive. It does not reinforce the sick role, nor does it signal advancing disease as nearly as much as parenteral administration does for many patients. Oral opioids are subject to hepatic first-pass metabolism because orally administered drugs must pass through the liver before reaching the systemic circulation. When that occurs, larger doses of drug are needed than with parenteral routes. Most immediate-release oral opioid formulations have an onset of analgesia of about 20 to 40 minutes for most patients, with peak analgesia occurring about 45 to 60 minutes post-administration. Oral morphine is reported to require 30 to 45 minutes to reach a peak plasma level, whereas oxycodone levels may take 60 to 90 minutes to peak after oral administration.25 Delayed peak serum concentrations would seem to make oral opioids less than ideal for managing breakthrough pain.25 Experience, however, has shown that not to be the case; oral opioids usually can effectively manage breakthrough pain. Morphine and oxycodone are available in controlled-release formulations that provide extended pain relief without the need for doses every 4 hours. Methadone and levorphanol are options for long-acting pain management due to the inherently long half-lives of these medications.

Most opioids can be administered rectally when the oral route is not feasible. Rectal administration avoids the hepatic first-pass effect if the dosage form is administered correctly. Three sets of veins are responsible for rectal blood return: the superior, middle, and inferior rectal veins. The rectal superior vein is responsible for the upper portion of the rectum (approximately 15 to 20 cm high) and returns blood to the portal vein that leads to immediate hepatic metabolism. The middle and inferior rectal veins return blood to the inferior vena cava. Drug administration into the lower rectal vault allows for larger amounts of the parent drug to reach the systemic circulation without being affected by the first-pass effect.26,27 Hydromorphone, morphine, and oxymorphone are commercially available as rectal suppositories. Controlled-release morphine tablets have been used rectally with good results at essentially the same doses as are used orally.28

Lipophilicity favors absorption across biological surfaces including the skin and oral mucosa. The more lipophilic opioids (e.g., fentanyl) pass across these surfaces easier and faster than the more hydrophilic opioids (e.g., morphine). Transdermal fentanyl patches permit simple and convenient administration of drug to patients unable to take opioids orally or rectally. The analgesic releases from the gel matrix patch into subcutaneous fat that serves as an in vivo drug reservoir from which the drug is released into the serum slowly over 2 to 3 days. After patch application, serum levels rise slowly. The average time to relative steady-state serum levels following transdermal fentanyl administration ranges form 15 to 20 hours.29 Once the patch is removed, the drug continues to move into the serum from the subcutaneous fat depot. Serum fentanyl levels decrease slowly; effects may continue for 12 to 24 hours after patch removal. These pharmacokinetic factors make transdermal fentanyl a poor option for patients with rapidly changing opioid requirements.

Oral transmucosal fentanyl has been commercially available for several years as a lozenge on a handle for both preoperative and preprocedural pain management. Another oral lozenge on a handle dosage form was more recently approved for managing breakthrough cancer pain. Initially, about 25% of the transmucosal dose is readily absorbed across the buccal mucosa. Because some of the medication trickles down the throat and is absorbed from the GI tract, an additional 25% (one third of the remaining 75%) is available systemically after metabolism. Systemic bioavailability is generally considered to be about 50% of an administered dose. Onset of analgesia occurs in 5 to 10 minutes, with a peak effect in 20 to 40 minutes. Other opioids, including morphine and methadone, have been administered as concentrated aqueous sublingual or buccal solutions. Larger doses often are required for morphine and other hydrophilic compounds when they are administered across the oral mucosa. Table 58-4 lists bioavailability variables and data for sublingual opioid administration.

Intravenous opioids provide 100% bioavailability by definition. Subcutaneous opioid infusion provides similar drug levels to those achieved with intravenous infusion.30 Subcutaneous and intramuscular injections provide similar pharmacokinetics as well. Time to peak effect for intramuscular and subcutaneous administration is delayed due to the need for absorption, but these two routes provide similar levels at similar times. As with transdermal delivery, the more lipophilic compounds (e.g., fentanyl) act more rapidly after injection. Absorption of opioids from the intramuscular route is a rate-limiting step, for which lipophilicity is a major factor. Intramuscular injections are not recommended due to the pain and possible tissue damage they can inflict. Additionally, absorption from intramuscular injections can be erratic.

Distribution

Opioid distribution is a function of plasma protein binding and lipophilicity. Morphine is 30% to 35% bound to plasma proteins and does not appear to be influenced greatly by displacement, a pharmacodynamic factor. Morphine does not remain in tissues for an extended time. Fentanyl is both highly protein bound (80% to 85%) and quite lipophilic. The free fraction of fentanyl increases in acidosis. Fentanyl also distributes to fat tissue throughout the body from which it redistributes slowly into the systemic circulation.

Metabolism (Biotransformation) and Elimination (Excretion)

Opioids that are not readily eliminated by the kidneys in the parent form are metabolized to form more water-soluble metabolites. The liver metabolizes opioids by numerous processes, including dealkylation, glucoronidation, hydrolysis, and oxidation. Opioids are also metabolized to a minor extent in other body compartments, for example, central nervous system, kidneys, lungs, and placenta. The metabolic fate of a number of pain medications impacts the selection of an appropriate therapeutic regimen (Table 58-5). Some metabolites can cause untoward neurotoxicity,31 and may displace the more active parent compound from opioid-receptor sites. Many patients are at risk from the toxicities of metabolite accumulation, especially patients with impaired renal function (which includes most elderly individuals) and those receiving high-dose or long-term opioid therapy.

Accumulation of normeperidine, a metabolite of meperidine, causes neurotoxicity, especially in elderly patients and in those with poor renal function. Use of meperidine should be limited to 1 to 2 days for acute pain, and should be avoided in the management of chronic pain.

In man, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the two major morphine metabolites.32 As much as 50% of the parent drug may be renally excreted as M3G, whereas M6G accounts for about 5%.33 Both compounds are water-soluble glucuronides that depend on renal elimination for clearance. M3G appears to be antinociceptive and has been associated with hyperalgesia and neurotoxicities including myoclonus.31,34 M6G possesses analgesic properties, and may be significantly more potent than morphine. Accumulation of both metabolites, as a function of poor renal status, predisposes patients to toxicity as well as poor pain control.

Normorphine, a desmethyl metabolite of morphine, may contribute to the toxic effects seen with high-dose or long-term morphine use. However, reports of normorphine accumulation indicate that M6G and M3G were also elevated.35 Therefore, whether normorphine accumulation contributes to toxicity remains unclear. It is unclear how often metabolites of other opioids may be problematic in renally impaired patients. Some authors have suggested that caution is advisable with hydromorphone due to metabolites, including the 3 and 6 glucuronides, and with fentanyl, which has a desmethyl metabolite.31 Oxycodone has only an active analgesic metabolite, hydromorphone, which may make oxycodone safer for some elderly and renally impaired patients.

The kidney accounts for about 90% of the excretion of an opioid (parent drug and metabolites) through the urine. Fecal elimination is a minor pathway and accounts for less than 10% of opioid excretion.

Pure μ-opioid agonists do not differ pharmacodynamically, but they do differ in their pharmacokinetic properties. All except codeine normally provide the same level of analgesia when dosed appropriately. For several reasons including genetic polymorphism, some patients respond better to some opioids than others. Clinical trial is the only way to determine a preferred alternative if a patient does not respond as expected to the initial choice. Pharmacokinetic properties and controlled-release formulations play major roles in the drugs’ fate in the organism.

As long as a noxious nociceptive stimulus that responds to opioids is present, these drugs should be used on a regular schedule or time-contingent basis. Undertreated acute pain can lead to chronic pain syndromes. Untreated or undertreated pain causes repeated stimulation of the CNS. Repeated stimulation of the afferent nociceptive neurons can sensitize both those neurons, producing the phenomenon known as physiologic windup, and cells in the dorsal horn of the spinal cord resulting in neuronal plasticity.36 Such sensitization can induce neurologic changes that last long after the initial insult has healed. Neuronal plasticity, or changes in the CNS, may lead to hyperalgesia. Windup is the progressive increase in the frequency of elicited action potentials seen in neurons as a result of a slowly repeated stimulus of C fibers.37 Long-term potentiation (LTP) is brief high-frequency stimuli that increase the efficiency of synaptic transmission.38 These processes lead to hyperalgesia as a consequence of central excitability. The use of around-the-clock opioids often breaks the cycle of pain, and can decrease or eliminate the centrally mediated processes that complicate pain control. Thus it may take less drug to prevent the recurrence of pain than would be required to treat recurring pain.

Morphine and the other pure opioid agonists can provide analgesia in most acute and chronic malignant pain patients and many chronic nonmalignant pain patients. There is no a priori maximum dose for any pure μ agonists. Patients require individual titration of medication regimens. Morphine dose requirements for comfort following similar noxious stimuli may vary 50- to 100-fold among chronic malignant pain patients,39 and 10- to 20-fold among acute pain patients.40

In addition to the regularly scheduled opioid doses, supplemental doses should be available for management of breakthrough pain. Breakthrough pain can be defined as transitory increases in pain greater than moderate intensity, occurring in addition to baseline pain of moderate or less intensity.41 Breakthrough pain regimens should be based on the background (time-contingent) dose, not on fixed doses. Sufficient rescue doses of the opioid should be available to the patient as immediate-release dosage forms to provide comfort when breakthrough pain occurs. Incidental pain often occurs predictably when a patient ambulates, gets tired, or undergoes medical procedures. In such cases, an additional dose of an oral, immediate-release dosage form should be administered to provide effective levels about a half-hour before the anticipated pain increase. For unpredictable breakthrough pain, a typical rescue dose order is one half of the every 4-hour scheduled dose (1/6 of the every 12-hour scheduled controlled-release dose) permitted every 2 hours as needed. When a patient with chronic pain requires more than two to three rescue doses for more than 2 to 3 days in succession, an increase in the time-contingent dose should be considered.

When escalation of an opioid dose is warranted, it is important to increase the dose as a percentage of the current regimen, not a set number of milligrams. Increases of 50% should be made as soon as steady-state serum levels are achieved (5 half-lives, which is equal to about 10 hours for morphine) after 5 days of scheduled opioid therapy. An increase from 30 mg every 4 hours to 45 mg every 4 hours would be appropriate. If the inadequate dose is 300 mg every 12 hours, the increase should be to 450 mg every 12 hours.

Clinicians should carefully evaluate complaints of increased pain or diminished analgesic effect in patients whose analgesia was adequate before simply increasing the opioid dose. Clinical tolerance to opioid analgesia in itself is uncommon once comfort has been achieved and maintained for a few days. Ineffective analgesia is almost always a result of factors that increase pain or compromise analgesic efficacy. These factors include progressive disease, new disease, increased or excessive activity, poor compliance, change in medication formulation or brand, drug interactions, and opioid addiction or diversion.42

Medications with long half-lives, such as methadone and levorphanol, can be useful for managing chronic pain syndromes. Typically these drugs afford analgesia for 8 hours or longer once steady-state serum levels are achieved. Methadone may be required every 4 hours during the first day of analgesic therapy, but can usually be administered every 8 to 12 hours in about 4 days. This longer duration is useful for providing time-contingent opioid therapy to patients with chronic pain who often become noncompliant with every 4-hour opioids after they have a few days of relative comfort. Because of the the long and variable half-life of methadone, clinicians should exercise caution. Patients may achieve adequate analgesia initially, but with continued use they may become toxic due to accumulation of methadone and its metabolites (Fig. 58-4). Methadone has little usefulness in acute pain due to its extended half-life.

Currently available μ agonists can be given orally, rectally, parenterally, transdermally, and transmucosally. The mixed agonist-antagonists are available in parenteral dosage forms. Pentazocine also is available in an oral tablet and butorphanol in a nasal spray. For the majority of patients taking time-contingent opioids, oral dosage forms are preferred agents. The oral route is easy to use, relatively inexpensive, does not signal increasing disease to the patient or family, and is effective. Incomplete bioavailability is not a concern since this limitation is easily overcome by increasing the dose. The only advantage of parenteral over oral administration for a patient able to take a drug orally is delivery of drug to sites of action more quickly. The time difference to analgesic onset and peak levels between oral administration and intramuscular or subcutaneous injections is often negligible. With appropriate scheduling, each dose of opioid can be administered sufficiently in advance of the prior dose to prevent recurrence of pain.

Patients and clinicians often hold false beliefs regarding potency and routes of administration, that is, parenteral versus oral. While intravenous administration affords quicker onset, it does not increase potency. The psychological advantage of oral administration should not be minimized. Fear of loss of control—epitomized by the need to depend on others to administer analgesics—is a major cause of depression among chronic and terminally ill pain patients.

Patients unable to tolerate oral administration often do well on administration, especially in short-term and terminal care. Hydromorphone, morphine, and oxymorphone are commercially available in rectal suppositories. Controlled-release oral morphine tablets have been used effectively via the rectal route27 (Table 58-6). Mucosal irritation may occur in fewer patients with rectally administered oral controlled-release morphine tablets than with commercial morphine suppositories.28 No local side effects were noted in a report of controlled-release oral morphine administered rectally.43

It is important to insert suppositories and tablets just above the anal sphincter to minimize first-pass metabolism. The inferior and middle rectal veins do not drain into the portal circulation as do the superior rectal veins. Administration higher into the rectal vault could induce a partial first-pass effect, which would lessen the effectiveness of the dose.27 As with any rectal dosage administration, patients receiving opioids by this route should lie quietly on their sides for about 15 minutes after administration to aid absorption and minimize risk of rectal expulsion of the dose. Rectal administration of oral liquids may be an option in some patients; however, limitations on acceptable rectal fluid volumes and aesthetics may limit this option.

Another effective and noninvasive route for opioid administration is transdermal. Fentanyl is the only opioid currently available for transdermal administration. Transdermal fentanyl patches are indicated for management of chronic pain in patients tolerant to the respiratory depressant effects of opioids. They provide 72 hours of clinically effective CNS opioid levels in most cases, but some patients get only about 48 hours of relief from a patch. Although the patches are more expensive than oral dosage forms, they are a convenient and cost-effective alternative to parenteral opioids. Transdermal fentanyl can be used by patients unable or unwilling to use oral or rectal opioids. The patch can also be useful for patients with noncompliant behaviors, for example, patients who cannot remember to take their opioid. As mentioned previously, this dosage form can be problematic in patients who require rapid-dose titration or have rapidly changing analgesic requirements.44,45

Subcutaneous delivery offers a fairly easy and inexpensive mechanism to deliver opioids. The pharmacokinetics of subcutaneous delivery are quite similar to intramuscular administration for opioids, without the disadvantage of painful intramuscular injections. Subcutaneous delivery is common in hospice and palliative care, where it has been shown to provide a good alternative to the intravenous route. Subcutaneous administration should replace intramuscular administration for opioids.5

Intravenous opioid administration is especially useful following surgery and trauma. Intravenous patient-controlled analgesia (PCA) is routinely used in many acute settings, especially for postoperative analgesia. While intravenous opioids are warranted when gastrointestinal function is limited (e.g., postoperative ileus), the intravenous route can negatively reinforce the sick role in patients with chronic pain and those requiring end-of-life care. The major reported advantage of intravenous PCA over regularly scheduled injections is that PCA provides a sense of control for the patient. PCA offers no pharmacologic advantage over regularly scheduled oral opioids for patients able to tolerate oral medications.46

Spinal administration of opioids is warranted in a small number of patients. It avoids the toxicity associated with the systemic delivery of these medications. The epidural and intrathecal routes each have advantages and disadvantages. Epidural administration allows opioid placement at any dermatomal level and does not require puncturing of the dura. Larger doses, however, are required and systemic effects may occur with epidural administration, increasing the risk of adverse effects. For morphine, intrathecal doses are only 1/10 of those needed for an equianalgesic epidural dose. Intrathecal administration requires puncturing of the dura and placing the drug closer to the spinal cord receptors. Drawbacks to intrathecal use include increased potential for meningitis and risk of postdural puncture headaches. Dose-related problems associated with spinal analgesia include pruritis, urinary retention, and delayed respiratory depression. Spinal analgesia is discussed in depth in Chapter 71.

Transmucosal delivery of fentanyl is useful for managing rapidly escalating breakthrough pain. This route produces rapid serum levels of lipophilic opioids and is useful for both preoperative and preprocedural sedation as well as analgesia. Oral transmucosal fentanyl provides rapid onset because there is no submucosal fat layer in the mouth. Because of the rapid onset of action, transmucosal fentanyl may prove to be beneficial as a breakthrough medication for patients who are on time-contingent opioid regimens. Oral transmucosal forms of fentanyl is commercially available as lozenges on handles. They do not resemble lollipops and should not be referred to as such in order to minimize the risk of children assuming they are candy. This dosage form (Actiq) is indicated for breakthrough pain in cancer patients and is available in a range of strengths (See Table 58-2).

Sublingual opioid administration has been used extensively in palliative care. Advantages include ease of administration, low expense (with oral, not parenteral, solutions), avoidance of hepatic first pass, and rapid onset of action (˜5 to 15 minutes). Disadvantages include relatively low bioavailability, potential for poor taste acceptance, and the need to avoid drinking anything for about 15 minutes following administration. Simple aqueous solutions are most appropriate for this route. The volume of a dose should not exceed 1 mL to minimize medication trickling down the throat. If a larger amount of medication is needed than will readily dissolve in 1 mL of water, a second dose can be given after 5 to 10 minutes. In a study of the percentage of sublingual opioid absorbed after 1 mL of an aqueous solution was held in the mouth for 10 minutes at pH 6.5, absorption was greater for lipophilic than hydrophilic opioids. Results from that study are listed in Table 58-4.47 As the mouth pH increased, absorption increased. Opioids often taste bitter, but many patients find overly sweet solutions even less palatable. Mild citrus or bland flavors are usually most acceptable. Changes in the oral mucosa, stomatitis, increased keratinization, decreased salivary flow, and changes in salivary pH due to disease, trauma, radiation or chemotherapy, as well as the overall condition of the mouth, influence absorption from sublingual, buccal, and oral transmucosal administration.

Nebulization into the lungs, and intravaginal use of oral tablets and rectal suppositories have been reported. Nebulized morphine has been shown to be useful in the setting of dyspnea, especially in terminally ill patients.48 However, systemic opioids may be required to effectively treat cough.49 The use of oral and rectal morphine formulations via the vagina has been studied.50 Because of the unpredictable bioavailability resulting from vaginal delivery, this route is not recommended. Intrastomal administration has been used with reported success by some hospice programs. Drug level data from this route have not been reported.

Opioids interact with a variety of medications (Table 58-7). Most opioid drug interactions are a consequence of additive effects, that is, pharmacodynamic interactions. Increases in sedation can be seen when opioids are administered with alcohol, benzodiazepines, butyrophenones, phenothiazines, sedative hypnotics, and tricyclic antidepressants. Midazolam may decrease the effect of fentanyl.51 Antinociceptive activity may be impaired by benzodiazepine administration from inhibition of the descending inhibitory control pathways.51

Methadone withdrawal has been precipitated by a number of agents known to induce microsomal enzymes.52 This pharmacokinetic interaction results in an increase in the metabolism of methadone. Inhibition of methadone metabolism has also been shown with several agents, leading to increased plasma levels of methadone.

Opioids can inhibit metabolism of other agents, leading to increases in serum levels of affected drugs. Desipramine plasma levels may be increased by coadministration with methadone or morphine.51,52

A World Health Organization (WHO) Expert Committee defined five principles of opioid use in 1986 to manage cancer pain in developing countries (WHO Cancer Pain Relief 1986, 1996). Those principles have been validated numerous times in undeveloped, developing, and developed countries including the United States.53–61 More recently, the applicability of these principles in both acute pain5 and chronic noncancer pain has been documented.8 These principles may be summarized as:

• 1. Use oral or other noninvasive routes whenever possible.
• 2. Individualize doses by titrating to response.
• 3. Select analgesics according to needs as described on the analgesic ladder.
• 4. Maintain effective drug levels in the body as long as there is a noxious stimulus.
• 5. Use indicated adjuvants.

The usefulness of this approach has been studied in over 2100 cancer patients treated over a period of 10 years for a total of 140,478 treatment days. Drugs on step 1 of the WHO analgesic ladder provided adequate analgesia for only 11% of the days, step 2 for 31% of the days, and step 3 for 49% of the treatment days. Fifty-six percent of the patients received morphine. Co-analgesics including antidepressants, anticonvulsants, and corticosteroids were used on 37% of the treatment days and drugs for other symptoms, such as laxatives, were used on 79% of the treatment days. In their final days of life, 84% of the patients rated their pain as moderate or less.60

A 1998 study of over 4000 cancer patients with documented daily pain who were residents in over 1400 nursing homes in five midwestern American states revealed serious underuse of opioids in managing pain. Sixteen percent received only acetaminophen or an NSAID, 32% received WHO analgesic ladder step 2 drug therapy, and only 26% received morphine. Fully 26% of these patients received no analgesia.10 With the WHO and AHCPR guidelines on use of opioids having been available for so long, it is difficult to understand how such inadequate use of these drugs continues.

Many health professionals subscribe to false beliefs about opioids. Unnecessary fears of addiction, dependence, tolerance, and toxicity often deter prescribing and taking of these important medications.

Addiction and Dependence

Until recently, most of what was known about opioid addiction was based on the experience of drug abusers, not patients. Opioids more commonly cause dysphoria than euphoria among opioid-naive individuals. Patients in pain seek comfort, not a drug-induced high. Studies of the actual incidence of iatrogenic opioid addiction show that this phenomenon is exquisitely rare. The Boston Collaborative Drug Surveillance Program study revealed only four cases of iatrogenic addiction among 11,882 patients without prior history of substance abuse who received opioids for a broad range of indications and were followed for up to 2 years.62 A national survey of over 10,000 burn patients without prior histories of drug abuse who received opioids for extended periods revealed no cases of addiction.63 Only 3 of 2369 chronic headache patients, most of whom had access to opioids, abused the analgesics.64

Addiction is defined as the compulsive use of a substance resulting in physical, psychological, or social harm and continued use despite that harm.65 Drug-seeking behavior does not in itself indicate addiction. Pseudoaddiction was defined over a decade ago as a drug-seeking behavior due to inadequate analgesia, not substance abuse.66 The American Society of Addiction Medicine said in its April 1997 Public Policy Statement that “. . individuals who have severe, unrelieved pain may become intensely focused on finding relief for their pain. Sometimes, such patients may appear to observers to be preoccupied with obtaining opioids, but the preoccupation is with finding relief of pain, rather than using opioids, per se. This phenomenon has been termed pseudoaddiction.”67

Dependence is defined as a physiologic phenomenon characterized by an abstinence syndrome upon abrupt discontinuation, substantial dose reduction, or administration of an antagonist.65 Dependence occurs predictably among patients who take opioids on a regular basis for more than a few days. It also occurs predictably among patients taking steroids and many other common drugs. Opioid dependence can usually be ended by tapering the dose over 5 to 10 days when the drug is no longer needed.68 It should not be a barrier to use of the drugs when they are indicated. Neither dependence nor tolerance is indicative of or a predisposing factor to addiction.

Tolerance

Tolerance to opioids is widely misunderstood. Three distinct types of tolerance occur with opioids. Tolerance to the respiratory depressive effects and other manifestations of CNS depression normally occurs within 5 to 7 days of continuous, regularly scheduled opioid use. Such patients are commonly referred to as being opioid-tolerant. Tolerance to the constipating effects of opioids does not occur.69 Activated μ-opioid receptors in the colon inhibit peristalsis. Stimulating laxatives, for example, senna, bisacodyl, are needed to induce colonic emptying. Stool softeners alone are not effective. Because of the risk of severe constipation and fecal impaction, prophylaxis with stimulating laxatives may be indicated when opioid therapy is started.70

It often is necessary to increase the opioid dose over the first few days or week of therapy while finding the effective dose. Tolerance to analgesia does not occur in most patients once the effective dose of opioid is identified and administered regularly. Neither up-nor down-regulation of opioid receptors occurs with regularly scheduled dosing. Most patients remain comfortable on a consistent opioid dose unless another variable occurs. When an otherwise stable opioid dose ceases to be effective, pseudotolerance due to increasing or new pathology, excessive physical activity after the pain decreases, drug interactions, noncompliance, or other nonpharmacologic factors should be considered.42

Multiple Pain Complaints

Many clinicians conclude that patients are abusing opioids when the patients complain of new pains once their initial pain complaints are controlled. In a study of 955 advanced cancer patients, 34% experienced two or more different types of pain, and 80% reported pain resulting from two or more different causes.71 Similar findings have been reported for AIDS patients.72 More severe pain tends to mask less intense pains. When the former is effectively treated, masked pains that require other treatment often become evident.

Save Opioids Until They Are Really Needed

A common false belief of patients is that use of opioids relatively early in the course of a progressive disease tends to render them less useful later when they may be needed more. That is not true. Pure μ opioids are effective over a broad clinical dosage range (Fig. 58-3). When pain increases, doses can be increased without loss of effectiveness.

Opioids Are Effective for All Types of Pain

Opioids are effective analgesics for most nociceptive and much neuropathic pain. But all pain is not opioid-responsive. Some pain that is opioid-responsive should not be managed with opioids, for example, constipation pain. The underlying cause of the pain should be treated before considering the sole use of opioids to control it. Examples of this include neuropathic pain for which tricyclic antidepressants, anticonvulsants, and nerve blocks may be indicated; painful infectious cysts for which incision and drainage followed by antiinfectives may be indicated; and gastrointestinal spasm for which anticholinergics may be most effective.73

Parenteral Opioids Are More Potent and Effective Than Oral Doses

Many patients believe that parenteral opioids are more effective than analgesics administered by oral or other noninvasive routes. As discussed earlier, this is not true. Furthermore, use of parenteral routes signals advancing disease to many patients and may be psychologically disadvantageous.

Potency is commonly misunderstood. Potency only indicates the amount of drug needed for effect. For example, 10 mg of oral morphine is approximately equal to 1.5 to 2 mg of oral hydromorphone. Hydromorphone is therefore about five times more potent, but no more effective, than morphine. When patients ask for more potent drugs, they usually mean more effective drugs.

Dose Increments Should Be Conservative

Fear of opioids causes many clinicians to use conservative dose increments. This can lead to treatment failure. Opioid doses should be increased to response. The appropriate increment is normally 50% of the dose, and this can be increased every five half-lives (twice a day for morphine). This percentage of increase applies no matter what the prior dose. When a patient knows that the opioid dose has been increased, but adequate analgesia dose not result, anxiety often increases. This increases the pain perception, which in turn increases the opioid dose requirement further. It is often better to err slightly in the direction of too much than too little opioid. Initial sedation may be advantageous when a patient is very anxious and experiencing a sleep deficit from the pain.

Opioids Prevent Safe Driving Due to Impaired Judgement and Psychomotor Function

Opioids can markedly impair judgement and psychomotor function when therapy is initiated. Similar adverse effects can occur when doses are increased. But once a patient has been continuously receiving opioids on a regular schedule for about a week, these effects usually diminish markedly. There was no significant difference in the number of motor vehicle crashes that involved 24 drivers who were taking opioids on a regular schedule for long-term pain management than among the general population of Finland.74 A recent systematic review of the world literature confirmed this finding.88 If the patient is experiencing no observable opioid-induced impairment and the opioid dose has been consistent for a week or more, the patient can usually drive or carry out other normal functions safely. When the dose is increased, however, the patient should refrain from those activities for about a week and until any impairment due to the increased dose resolves.

Opioids are important and commonly underused analgesic drugs. Health professionals, patients, and caregivers often harbor irrational fears about these drugs. Opiophobia has been defined as “irrational and undocumented fear that appropriate use of opioids causes addiction.”1 As a result, opioids are often underprescribed, underdosed, taken irregularly in spite of instructions to the contrary, and stopped abruptly. Inappropriate beliefs about opioids have been documented among physicians,75 nurses,76 and pharmacists.77 Societal barriers to the use of opioids are now being refuted by professional organizations8 and regulatory agencies.9 Nevertheless, many clinicians continue to avoid opioids in their practices to the detriment of their patients. Unlike nonsteroidal anti-inflammatory drugs and even acetaminophen, long-term opioid use rarely causes end-organ toxicity.

New opioids delivery systems including oral controlled release, iontophoretic, implanted, and transdermal dosage forms are currently under development. Combination dosage forms of opioids with other drugs also are being investigated. Some of these new forms may make opioid analgesia easier. But excellent analgesia can be provided with the drugs and dosage forms currently available. All pain clinicians can and should work to overcome opioid myths and misconceptions and should encourage appropriate use of opioids when they are indicated.