Opioid (narcotic) analgesics, opioid antagonists, and nonopioid centrally acting analgesics

Analgesics are drugs that relieve pain without causing loss of consciousness. In this chapter, we focus mainly on the opioid analgesics, the most effective pain relievers available. The opioid family, whose name derives from opium, includes such widely used agents as morphine, fentanyl, codeine, and oxycodone [OxyContin, others].

Opioid analgesics

Introduction to the opioids

TABLE 28–1

Important Responses to Activation of Mu and Kappa Receptors

	Receptor Type
Response	Mu	Kappa
Analgesia
Respiratory depression
Sedation
Euphoria
Physical dependence
Decreased GI motility

Mu receptors.

Responses to activation of mu receptors include analgesia, respiratory depression, euphoria, and sedation. In addition, mu activation is related to physical dependence.

A study in genetically engineered mice underscores the importance of mu receptors in drug action. In this study, researchers studied mice that lacked the gene for mu receptors. When these mice were given morphine, the drug had no effect. It did not produce analgesia or physical dependence, and it did not reinforce social behaviors that are thought to indicate subjective effects. Hence, at least in mice, mu receptors appear both necessary and sufficient to mediate the major actions of opioid drugs.

Kappa receptors.

As with mu receptors, activation of kappa receptors can produce analgesia and sedation. In addition, kappa activation may underlie psychotomimetic effects seen with certain opioids.

Classification of drugs that act at opioid receptors

Drugs that act at opioid receptors are classified on the basis of how they affect receptor function. At each type of receptor, a drug can act in one of three ways: as an agonist, partial agonist, or antagonist. (Recall from Chapter 5 that a partial agonist is a drug that produces low to moderate receptor activation when administered alone, but will block the actions of a full agonist if the two are given together.) Based on these actions, drugs that bind opioid receptors fall into three major groups: (1) pure opioid agonists, (2) agonist-antagonist opioids, and (3) pure opioid antagonists. The actions of drugs in these groups at mu and kappa receptors are summarized in Table 28–2.

TABLE 28–2

Drug Actions at Mu and Kappa Receptors

	Receptor Type
Drugs	Mu	Kappa
Pure Opioid Agonists
Morphine, codeine, meperidine, and other morphine-like drugs	Agonist	Agonist
Agonist-Antagonist Opioids
Pentazocine, nalbuphine, butorphanol	Antagonist	Agonist
Buprenorphine	Partial agonist	Antagonist
Pure Opioid Antagonists
Naloxone, naltrexone, others	Antagonist	Antagonist

Pure opioid agonists.

The pure opioid agonists activate mu receptors and kappa receptors. By doing so, the pure agonists can produce analgesia, euphoria, sedation, respiratory depression, physical dependence, constipation, and other effects. As indicated in Table 28–3, the pure agonists can be subdivided into two groups: strong opioid agonists and moderate to strong opioid agonists. Morphine is the prototype of the strong agonists. Codeine is the prototype of the moderate to strong agonists.

TABLE 28–3

Opioid Analgesics: Abuse Liability and Maximal Pain Relief

Drug and Category	CSA* Schedule	Abuse Liability	Maximal Pain Relief
Strong Opioid Agonists
Alfentanil	II	High	High
Fentanyl	II	High	High
Hydromorphone	II	High	High
Levorphanol	II	High	High
Meperidine	II	High	High
Methadone	II	High	High
Morphine	II	High	High
Oxymorphone	II	High	High
Remifentanil	II	—	High
Sufentanil	II	High	High
Moderate to Strong Opioid Agonists
Codeine	II	Moderate	Low
Hydrocodone	III^†	Moderate	Moderate
Oxycodone	II	Moderate	Moderate to high
Tapentadol	II	Moderate	Moderate to high
Agonist-Antagonist Opioids
Buprenorphine	V	Low	Moderate to high
Butorphanol	IV	Low	Moderate to high
Nalbuphine	NR^‡	Low	Moderate to high
Pentazocine	IV	Low	Moderate

^*CSA = Controlled Substances Act.

^†In the United States, hydrocodone is available only in combination with aspirin or acetaminophen. These combination products are classified under Schedule III.

^‡NR = not regulated under the Controlled Substances Act.

Agonist-antagonist opioids.

Four agonist-antagonist opioids are available: pentazocine, nalbuphine, butorphanol, and buprenorphine. The actions of these drugs at mu and kappa receptors are summarized in Table 28–2. When administered alone, the agonist-antagonist opioids produce analgesia. However, if given to a patient who is taking a pure opioid agonist, these drugs can antagonize analgesia caused by the pure agonist. Pentazocine [Talwin] is the prototype of the agonist-antagonists.

Pure opioid antagonists.

The pure opioid antagonists act as antagonists at mu and kappa receptors. These drugs do not produce analgesia or any of the other effects caused by opioid agonists. Their principal use is reversal of respiratory and CNS depression caused by overdose with opioid agonists. In addition, one of these drugs—methylnaltrexone—is used to treat opioid-induced constipation. Naloxone [Narcan] is the prototype of the pure opioid antagonists.

Basic pharmacology of the opioids

Morphine

Morphine is the prototype of the strong opioid analgesics and remains the standard by which newer opioids are measured. Morphine has multiple pharmacologic effects, including analgesia, sedation, euphoria, respiratory depression, cough suppression, and suppression of bowel motility. The drug is named after Morpheus, the Greek god of dreams.

Source

Morphine is found in the seedpod of the poppy plant, Papaver somniferum. The drug is prepared by extraction from opium (the dried juice of the poppy seedpod). In addition to morphine, opium contains two other medicinal compounds: codeine (an analgesic) and papaverine (a smooth muscle relaxant).

Overview of pharmacologic actions

Morphine has multiple pharmacologic actions. In addition to relieving pain, the drug causes drowsiness and mental clouding, reduces anxiety, and creates a sense of well-being. Through actions in the CNS and periphery, morphine can cause respiratory depression, constipation, urinary retention, orthostatic hypotension, emesis, miosis, cough suppression, and biliary colic. With prolonged use, the drug produces tolerance and physical dependence.

Individual effects of morphine may be beneficial, detrimental, or both. For example, analgesia is clearly beneficial, whereas respiratory depression and urinary retention are clearly detrimental. Certain other effects, such as sedation and reduced bowel motility, may be beneficial or detrimental, depending on the circumstances of drug use.

Therapeutic use: relief of pain

The principal indication for morphine is relief of moderate to severe pain. The drug can relieve postoperative pain, pain of labor and delivery, and chronic pain caused by cancer and other conditions. In addition, morphine can be used to relieve pain of myocardial infarction and dyspnea associated with left ventricular failure and pulmonary edema—although it is no longer the drug of choice for these disorders. Morphine may also be administered preoperatively for sedation and reduction of anxiety.

Morphine relieves pain without affecting other senses (eg, sight, touch, smell, hearing) and without causing loss of consciousness. The drug is more effective against constant, dull pain than against sharp, intermittent pain. However, even sharp pain can be relieved by large doses. The ability of morphine to cause mental clouding, sedation, euphoria, and anxiety reduction can contribute to relief of pain.

The use of morphine and other opioids to relieve pain is discussed further in this Chapter (under Clinical Use of Opioids) and in Chapter 29 (Pain Management in Patients with Cancer).

Mechanism of analgesic action.

Morphine and other opioid agonists appear to relieve pain by mimicking the actions of endogenous opioid peptides, primarily at mu receptors. This hypothesis is based on the following observations:

• Opioid peptides and morphine-like drugs both produce analgesia when administered to experimental subjects.

• Opioid peptides and morphine-like drugs share structural similarities (Fig. 28–1).

Figure 28–1 Structural similarity between morphine and met-enkephalin.
In the morphine structural formula, highlighting indicates the part of the molecule thought responsible for interaction with opioid receptors. In the met-enkephalin structural formula, highlighting indicates the region of structural similarity with morphine.

• Opioid peptides and morphine-like drugs bind to the same receptors in the CNS.

• The receptors to which opioid peptides and morphine-like drugs bind are located in regions of the brain and spinal cord associated with perception of pain.

• Subjects rendered tolerant to analgesia from morphine-like drugs show cross-tolerance to analgesia from opioid peptides.

• The analgesic effects of opioid peptides and morphine-like drugs can both be blocked by the same antagonist: naloxone.

From these data we can postulate that (1) opioid peptides serve a physiologic role as modulators of pain perception, and (2) morphine-like drugs produce analgesia by mimicking the actions of endogenous opioid peptides.

Adverse effects

Respiratory depression.

Respiratory depression is the most serious adverse effect. At equianalgesic doses, all of the pure opioid agonists depress respiration to the same extent. Death following overdose is almost always from respiratory arrest. Opioids depress respiration primarily through activation of mu receptors, although activation of kappa receptors also contributes.

The time course of respiratory depression varies with route of administration. Depressant effects begin about 7 minutes after IV injection, 30 minutes after IM injection, and up to 90 minutes after subQ injection. With all three routes, significant depression may persist for 4 to 5 hours. When morphine is administered by spinal injection, onset of respiratory depression may be delayed for hours; be alert to this possibility.

With prolonged use of opioids, tolerance develops to respiratory depression. Huge doses that would be lethal to a nontolerant individual have been taken by opioid addicts without noticeable effect. Similarly, tolerance to respiratory depression develops during long-term clinical use of opioids (eg, in patients with cancer).

When administered at usual therapeutic doses, opioids rarely cause significant respiratory depression. However, although uncommon, substantial respiratory depression can nonetheless occur. Accordingly, respiratory rate should be determined prior to opioid administration. If the rate is 12 breaths per minute or less, the opioid should be withheld and the prescriber notified. Certain patients, including the very young, the elderly, and those with respiratory disease (eg, asthma, emphysema) are especially sensitive to respiratory depression, and hence must be monitored closely. Outpatients should be informed about the risk of respiratory depression and instructed to notify the prescriber if respiratory distress occurs.

Respiratory depression is increased by concurrent use of other drugs with CNS-depressant actions (eg, alcohol, barbiturates, benzodiazepines). Accordingly, these drugs should be avoided. Outpatients should be warned against use of alcohol and all other CNS depressants.

Pronounced respiratory depression can be reversed with naloxone [Narcan], an opioid antagonist (see below). However, dosing must be carefully titrated. Why? Because excessive doses will completely block the analgesic effects of morphine, thereby causing pain to return.

Constipation.

Opioids promote constipation through actions in the CNS and GI tract. Specifically, by anticipating mu receptors in the gut, these drugs can suppress propulsive intestinal contractions, intensify nonpropulsive contractions, increase the tone of the anal sphincter, and inhibit secretion of fluids into the intestinal lumen. As a result, constipation can develop after a few days of opioid use. Potential complications of constipation include fecal impaction, bowel perforation, rectal tearing, and hemorrhoids.

Opioid-induced constipation can be managed with a combination of pharmacologic and nonpharmacologic measures. The goal is to produce a soft, formed stool every 1 to 2 days. Principal nondrug measures are physical activity and increased intake of fiber and fluids (for prevention) and enemas (for treatment). Most patients also require prophylactic drugs: A stimulant laxative, such as senna, is given to counteract reduced bowel motility; a stool softener, such as docusate [Colace, others] plus polyethylene glycol (an osmotic laxative) can provide additional benefit. If these prophylactic drugs prove inadequate, the patient may need rescue therapy with a strong osmotic laxative, such as lactulose or sodium phosphate. As a last resort, patients may be given methylnaltrexone [Relistor], an oral drug that blocks mu receptors in the intestine. As discussed later in the chapter, methylnaltrexone can’t cross the blood-brain barrier, and hence does not reverse opioid-induced analgesia.

Because of their effects on the intestine, opioids are highly effective for treating diarrhea. In fact, antidiarrheal use of these drugs preceded analgesic use by centuries. The impact of opioids on intestinal function is an interesting example of how an effect can be detrimental (constipation) or beneficial (relief of diarrhea) depending on who is taking the medication. Opioids employed specifically to treat diarrhea are discussed in Chapter 80.

Orthostatic hypotension.

Morphine-like drugs lower blood pressure by blunting the baroreceptor reflex and by dilating peripheral arterioles and veins. Peripheral vasodilation results primarily from morphine-induced release of histamine. Hypotension is mild in the recumbent patient but can be significant when the patient stands up. Patients should be informed about symptoms of hypotension (lightheadedness, dizziness) and instructed to sit or lie down if they occur. Also, patients should be informed that hypotension can be minimized by moving slowly when changing from a supine or seated position to an upright position. Patients should be warned against walking if hypotension is substantial. Hospitalized patients may require ambulatory assistance. Hypotensive drugs can exacerbate opioid-induced hypotension.

Urinary retention.

Morphine can cause urinary hesitancy and urinary retention. Three mechanisms are involved. First, morphine increases tone in the bladder sphincter. Second, morphine increases tone in the detrusor muscle, thereby elevating pressure within the bladder, causing a sense of urinary urgency. Third, in addition to its direct effects on the urinary tract, morphine may interfere with voiding by suppressing awareness of bladder stimuli. To reduce discomfort, patients should be encouraged to void every 4 hours. Urinary hesitancy or retention is especially likely in patients with prostatic hypertrophy. Drugs with anticholinergic properties (eg, tricyclic antidepressants, antihistamines) can exacerbate the problem.

Urinary retention should be assessed by monitoring intake and output and by palpating the lower abdomen every 4 to 6 hours for bladder distention. If a change in intake/output ratio develops, or if bladder distention is detected, or if the patient reports difficulty voiding, the prescriber should be notified. Catheterization may be required.

In addition to causing urinary retention, morphine may decrease urine production. How? Largely by decreasing renal blood flow, and partly by promoting release of antidiuretic hormone.

Cough suppression.

Morphine-like drugs act at opioid receptors in the medulla to suppress cough. Suppression of spontaneous cough may lead to accumulation of secretions in the airway. Accordingly, patients should be instructed to actively cough at regular intervals. Lung status should be assessed by auscultation for rales. The ability of opioids to suppress cough is put to clinical use in the form of codeine- and hydrocodone-based cough remedies.

Biliary colic.

Morphine can induce spasm of the common bile duct, causing pressure within the biliary tract to rise dramatically. Symptoms range from epigastric distress to biliary colic. In patients with pre-existing biliary colic, morphine may intensify pain rather than relieve pain. Certain opioids (eg, meperidine) cause less smooth muscle spasm than morphine, and hence are less likely to exacerbate biliary colic.

Emesis.

Morphine promotes nausea and vomiting through direct stimulation of the chemoreceptor trigger zone of the medulla. Emetic reactions are greatest with the initial dose and then diminish with subsequent doses. Nausea and vomiting are uncommon in recumbent patients, but occur in 15% to 40% of ambulatory patients, suggesting a vestibular component. Nausea and vomiting can be reduced by pretreatment with an antiemetic (eg, prochlorperazine) and by having the patient remain still.

Elevation of intracranial pressure.

Morphine can elevate intracranial pressure (ICP). The mechanism is indirect: By suppressing respiration, morphine increases the CO₂ content of blood, which dilates the cerebral vasculature, causing ICP to rise. Accordingly, if respiration is maintained at a normal rate, ICP will remain normal too.

Euphoria/dysphoria.

Euphoria is defined as an exaggerated sense of well-being. Morphine often produces euphoria when given to patients in pain. Although euphoria can enhance pain relief, it also contributes to the drug’s potential for abuse. Euphoria is caused by activation of mu receptors.

In some individuals, morphine causes dysphoria (a sense of anxiety and unease). Dysphoria is uncommon among patients in pain, but may occur when morphine is taken in the absence of pain.

Sedation.

When administered to relieve pain, morphine is likely to cause drowsiness and some mental clouding. Although these effects can complement analgesic actions, they can also be detrimental. Outpatients should be warned about CNS depression and advised to avoid hazardous activities (eg, driving) if sedation is significant. Sedation can be minimized by (1) taking smaller doses more often, (2) using opioids that have short half-lives, and (3) giving small doses of a CNS stimulant (methylphenidate or dextroamphetamine) in the morning and early afternoon. A nonamphetamine stimulant—modafinil [Provigil, Alertec] or armodafinil [Nuvigil]—may also be tried.

Miosis.

Morphine and other opioids cause pupillary constriction (miosis). In response to toxic doses, the pupils may constrict to “pinpoint” size. Since miosis can impair vision in dim light, room light should be kept bright during waking hours.

Birth defects.

Morphine and other opioids increase in the risk of serious birth defects by two- to threefold, although the absolute risk remains low. In 2011, the Centers for Disease Control and Prevention (CDC) released preliminary data showing that, when opioids are taken just before conception or during early pregnancy, they increase the risk of congenital heart defects, including atrioventricular septal defects, hypoplastic left heart syndrome, and conoventricular septal defects. In addition, opioids increase the risk of spina bifida and gastroschisis (protrusion of the intestine through the abdominal wall near the umbilicus). Clearly, opioids should be avoided prior to and during pregnancy.

Neurotoxicity.

Opioid-induced neurotoxicity can cause delirium, agitation, myoclonus, hyperalgesia, and other symptoms. Primary risk factors are renal impairment, pre-existing cognitive impairment, and prolonged, high-dose opioid use. Management consists of hydration and dose reduction. For patients who must take opioids long term, opioid rotation (periodically switching from one opioid to another) may reduce neurotoxicity development.

Adverse effects from prolonged use.

Clinical and preclinical studies indicate that prolonged use of opioids can cause hormonal changes and can alter immune function. Hormonal changes include a progressive decline in cortisol levels, an increase in prolactin levels, and a decrease in levels of luteinizing hormone, follicle-stimulating hormone, testosterone, and estrogen. With prolonged opioid exposure, immune function is suppressed. Are these changes clinically relevant? We don’t really know.

Pharmacokinetics

Morphine is administered by several routes: oral, IM, IV, subQ, epidural, and intrathecal. Onset of effects is slower with oral dosing than with parenteral dosing. With three routes—IM, IV, and subQ—analgesia lasts 4 to 5 hours. With two routes—epidural and intrathecal—analgesia may persist up to 24 hours. With oral therapy, duration depends on the formulation. For example, with immediate-release (IR) tablets, effects last 4 to 5 hours, whereas with extended-release (ER) capsules, effects last 24 hours.

In order to relieve pain, morphine must cross the blood-brain barrier and enter the CNS. Because the drug has poor lipid solubility, it does not cross the barrier easily. Consequently, only a small fraction of each dose reaches sites of analgesic action. Since the blood-brain barrier is not well developed in infants, these patients generally require lower doses than do older children and adults.

Morphine is inactivated by hepatic metabolism. When taken by mouth, the drug must pass through the liver on its way to the systemic circulation. Much of an oral dose is inactivated during this first pass through the liver. Consequently, oral doses need to be substantially larger than parenteral doses to achieve equivalent analgesic effects. In patients with liver disease, analgesia and other effects may be intensified and prolonged. Accordingly, it may be necessary to reduce the dosage or lengthen the dosing interval.

Tolerance and physical dependence

With continuous use, morphine can cause tolerance and physical dependence. These phenomena, which are generally inseparable, reflect cellular adaptations that occur in response to prolonged opioid exposure.

Tolerance.

Tolerance can be defined as a state in which a larger dose is required to produce the same response that could formerly be produced with a smaller dose. Alternatively, tolerance can be defined as a condition in which a particular dose now produces a smaller response than it did when treatment began. Because of tolerance, dosage must be increased to maintain analgesic effects.

Tolerance develops to many—but not all—of morphine’s actions. With prolonged treatment, tolerance develops to analgesia, euphoria, and sedation. As a result, with long-term therapy, an increase in dosage may be required to maintain these desirable effects. Fortunately, as tolerance develops to these therapeutic effects, tolerance also develops to respiratory depression. As a result, the high doses needed to control pain in the tolerant individual are not associated with increased respiratory depression.

Very little tolerance develops to constipation and miosis. Even in highly tolerant addicts, constipation remains a chronic problem, and constricted pupils are characteristic.

Cross-tolerance exists among the opioid agonists (eg, oxycodone, methadone, fentanyl, codeine, heroin). Accordingly, individuals tolerant to one of these agents will be tolerant to all the others. No cross-tolerance exists between opioids and general CNS depressants (eg, barbiturates, ethanol, benzodiazepines, general anesthetics).

Physical dependence.

Physical dependence is defined as a state in which an abstinence syndrome will occur if drug use is abruptly stopped. Opioid dependence results from adaptive cellular changes that occur in response to the continuous presence of these drugs. Although the exact nature of these changes is unknown, it is clear that, once these compensatory changes have taken place, the body requires the continued presence of opioids to function normally. If opioids are withdrawn, an abstinence syndrome usually will follow.

The intensity and duration of the opioid abstinence syndrome depends on two factors: the half-life of the drug being used and the degree of physical dependence. With opioids that have relatively short half-lives (eg, morphine), symptoms of abstinence are intense but brief. In contrast, with opioids that have long half-lives (eg, methadone), symptoms are less intense but more prolonged. With any opioid, the intensity of withdrawal symptoms parallels the degree of physical dependence.

For individuals who are highly dependent, the abstinence syndrome can be extremely unpleasant. Initial reactions include yawning, rhinorrhea, and sweating. Onset occurs about 10 hours after the final dose. These early responses are followed by anorexia, irritability, tremor, and “gooseflesh”—hence the term cold turkey. At its peak, the syndrome manifests as violent sneezing, weakness, nausea, vomiting, diarrhea, abdominal cramps, bone and muscle pain, muscle spasm, and kicking movements—hence, “kicking the habit.” Giving an opioid at any time during withdrawal rapidly reverses all signs and symptoms. Left untreated, the morphine withdrawal syndrome runs its course in 7 to 10 days. It should be emphasized that, although withdrawal from opioids is unpleasant, the syndrome is rarely dangerous. In contrast, withdrawal from general CNS depressants (eg, barbiturates, alcohol) can be lethal (see Chapter 34).

To minimize the abstinence syndrome, opioids should be withdrawn gradually. When the degree of dependence is moderate, symptoms can be avoided by administering progressively smaller doses over 3 days. When the patient is highly dependent, dosage should be tapered more slowly—over 7 to 10 days. With a proper withdrawal schedule, withdrawal symptoms will resemble those of a mild case of flu—even when the degree of dependence is high.

It is important to note that physical dependence is rarely a complication when opioids are taken acutely to treat pain. Hospitalized patients receiving morphine 2 to 3 times a day for up to 2 weeks show no significant signs of dependence. If morphine is withheld from these patients, no significant signs of withdrawal can be detected. The issue of physical dependence as a clinical concern is discussed further later in the chapter.

Infants exposed to opioids in utero may be born drug dependent. If the infant is not provided with opioids, an abstinence syndrome will ensue. Signs of withdrawal include excessive crying, sneezing, tremor, hyperreflexia, fever, and diarrhea. The infant can be weaned from drug dependence by administering dilute paregoric in progressively smaller doses.

Cross-dependence exists among pure opioid agonists. As a result, any pure agonist will prevent withdrawal in a patient who is physically dependent on any other pure agonist.

Abuse liability

Morphine and the other opioids are subject to abuse, largely because of their ability to cause pleasurable experiences (eg, euphoria, sedation, a sensation in the lower abdomen resembling orgasm). Physical dependence contributes to abuse: Once dependence exists, the ability of opioids to ward off withdrawal serves to reinforce their desirability in the mind of the abuser.

The abuse liability of the opioids is reflected in their classification under the Controlled Substances Act. (The provisions of this act are discussed in Chapter 37.) As shown in Table 28–3, morphine and all other strong opioid agonists are classified under Schedule II. This classification reflects a moderate to high abuse liability. The agonist-antagonist opioids have a lower abuse liability and hence are classified under Schedule IV (butorphanol, pentazocine) or Schedule V (buprenorphine), or have no classification at all (nalbuphine). Healthcare personnel who prescribe, dispense, and administer opioids must adhere to the procedures set forth in the Controlled Substances Act.

Fortunately, abuse is rare when opioids are employed to treat pain. The issue of abuse as a clinical concern is addressed in depth later in the chapter.

Precautions

Some patients are more likely than others to experience adverse effects. Common sense dictates that opioids be used with special caution in these people. Conditions that can predispose patients to adverse reactions are discussed immediately below.

Decreased respiratory reserve.

Because morphine depresses respiration, it can further compromise respiration in patients with impaired pulmonary function. Accordingly, the drug should be used with caution in patients with asthma, emphysema, kyphoscoliosis, chronic cor pulmonale, and extreme obesity. Caution is also needed in patients taking other drugs that can depress respiration (eg, barbiturates, benzodiazepines, general anesthetics).

Labor and delivery.

Use of morphine during delivery can suppress uterine contractions and cause respiratory depression in the neonate. Following delivery, respiration in the neonate should be monitored closely. Respiratory depression can be reversed with naloxone. The use of opioids in obstetrics is discussed in depth later in the chapter.

Neonatal opioid dependence.

Regular use of opioids during pregnancy can cause physical dependence in the fetus, resulting in signs of withdrawal a day or so after delivery. Signs of withdrawal include excessive crying, sneezing, tremor, fever, diarrhea, and hyperreflexia. The infant can be weaned by giving progressively smaller doses of dilute paregoric.

Head injury.

Morphine and other opioids must be used with caution in patients with head injury. Head injury can cause respiratory depression accompanied by elevation of ICP. Morphine can exacerbate these symptoms. In addition, since miosis, mental clouding, and vomiting can be valuable diagnostic signs following head injury, and since morphine can cause these same effects, use of opioids can confound diagnosis.

Other precautions.

Infants and elderly patients are especially sensitive to morphine-induced respiratory depression. In patients with inflammatory bowel disease, morphine may cause toxic megacolon or paralytic ileus. Since morphine and all other opioids are inactivated by liver enzymes, effects may be intensified and prolonged in patients with liver impairment. Severe hypotension may occur in patients with pre-existing hypotension or reduced blood volume. In patients with prostatic hypertrophy, opioids may cause acute urinary retention; repeated catheterization may be required.

Drug interactions

The major interactions between morphine and other drugs are summarized in Table 28–4. Some interactions are adverse, and some are beneficial.

TABLE 28–4

Interactions of Morphine-Like Drugs with Other Drugs

Interacting Drugs	Outcome of the Interaction
Adverse Interactions
CNS depressants Barbiturates Benzodiazepines Alcohol General anesthetics Antihistamines Phenothiazines	Increased respiratory depression and sedation
Agonist-antagonist opioids	Precipitation of a withdrawal reaction
Anticholinergic drugs Atropine-like drugs Antihistamines Phenothiazines Tricyclic antidepressants	Increased constipation and urinary retention
Hypotensive agents	Increased hypotension
Monoamine oxidase inhibitors	Hyperpyrexic coma
Beneficial Interactions
Amphetamines	Increased analgesia and decreased sedation
Antiemetics	Suppression of nausea and vomiting
Naloxone	Suppression of symptoms of opioid overdose
Dextromethorphan	Increased analgesia; possible reduction in tolerance

CNS depressants.

All drugs with CNS-depressant actions (eg, barbiturates, benzodiazepines, alcohol) can intensify sedation and respiratory depression caused by morphine and other opioids. Outpatients should be warned against use of alcohol and all other CNS depressants.

Anticholinergic drugs.

These agents (eg, antihistamines, tricyclic antidepressants, atropine-like drugs) can exacerbate morphine-induced constipation and urinary retention.

Hypotensive drugs.

Antihypertensive drugs and other drugs that lower blood pressure can exacerbate morphine-induced hypotension.

Monoamine oxidase inhibitors.

The combination of meperidine (a morphine-like drug) with a monoamine oxidase (MAO) inhibitor has produced a syndrome characterized by excitation, delirium, hyperpyrexia, convulsions, and severe respiratory depression. Deaths have occurred. Although this reaction has not been reported with combined use of an MAO inhibitor and morphine, prudence suggests that the combination should nonetheless be avoided.

Agonist-antagonist opioids.

Agonist-antagonist opioids (eg, pentazocine, buprenorphine) can precipitate a withdrawal syndrome if given to an individual physically dependent on a pure opioid agonist. The basis of this reaction is considered later in the chapter. Patients taking pure opioid agonists should be weaned from these drugs before beginning treatment with an agonist-antagonist.

Opioid antagonists.

Opioid antagonists (eg, naloxone) can counteract most actions of morphine and other pure opioid agonists. Opioid antagonists are employed primarily to treat opioid overdose. The actions and uses of the opioid antagonists are discussed in detail later in the chapter.

Other interactions.

Antiemetics of the phenothiazine type (eg, promethazine [Phenergan]) may be combined with opioids to reduce nausea and vomiting. Amphetamines, clonidine, and dextromethorphan can enhance opioid-induced analgesia. Amphetamines can also offset sedation.

Toxicity

Clinical manifestations.

Opioid overdose produces a classic triad of signs: coma, respiratory depression, and pinpoint pupils. Coma is profound, and the patient cannot be aroused. Respiratory rate may be as low as 2 to 4 breaths per minute. Although the pupils are constricted initially, they may dilate as hypoxia sets in (secondary to respiratory depression). Hypoxia may cause blood pressure to fall. Prolonged hypoxia may result in shock. When death occurs, respiratory arrest is almost always the immediate cause.

Treatment.

Treatment consists primarily of ventilatory support and giving an opioid antagonist. Naloxone [Narcan] is the traditional antagonist of choice. The pharmacology of the opioid antagonists is discussed later.

Preparations

Morphine alone.

Morphine sulfate, by itself, is available in 11 formulations:

• Immediate-release (IR) tablets (15 and 30 mg)

• Controlled-release tablets (15, 30, 60, 100, and 200 mg) sold as MS Contin and Oramorph SR

• Extended-release (ER) tablets (15, 30, 60, 100, and 200 mg)

• Sustained-release capsules (10, 20, 30, 50, 60, 80, 100, and 200 mg) sold as Kadian and Morphine SR

• Extended-release capsules (30, 60, 90, and 120 mg) sold as Avinza and M-Eslon

• Standard oral solution (10 and 20 mg/5 mL) sold as MSIR

• Concentrated oral solution (100 mg/5 mL) sold as MSIR and Roxanol

• Rectal suppositories (5, 10, 20, and 30 mg) sold as RMS and Statex

• Soluble tablets for injection (10, 15, and 30 mg)

• Standard solution for injection (0.5, 1, 2, 4, 5, 8, 10, 15, 25, and 50 mg/mL) sold as Astramorph PF, Duramorph, and Infumorph

• Extended-release liposomal solution for injection (10 mg/mL) sold as DepoDur

Morphine/naltrexone [embeda].

In 2010, the FDA approved Embeda, a fixed-dose combination of morphine and naltrexone, an opioid antagonist (see below). The product is designed to discourage morphine abuse. Embeda capsules are filled with tiny pellets that have an outer layer of extended-release morphine and an inner core of naltrexone. When the capsules are swallowed intact, only the morphine is absorbed. However, if the pellets are crushed, the naltrexone will be absorbed too, thereby blunting the effects of the morphine. As a result, potential abusers cannot get a quick high by crushing the pellets to release all of the morphine at once. However, abusers can still get high by simply taking a large dose. Embeda capsules are more expensive than other extended-release morphine products, and hence should be prescribed only when abuse appears likely.

Alcohol can accelerate release of morphine from Embeda pellets. As a result, the entire dose can be absorbed quickly—rather than over 24 hours—thereby causing a potentially fatal spike in morphine blood levels. Accordingly, patients should be warned against alcohol consumption.

Embeda capsules are available in six morphine/naltrexone strengths: 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, 80 mg/3.2 mg, and 100 mg/4 mg. Dosing is done once or twice daily. Patients can swallow Embeda capsules whole, or they can open the capsules and sprinkle the pellets on applesauce, which must be ingested without chewing.

Dosage and administration

General guidelines.

Dosage must be individualized. High doses are required for patients with a low tolerance to pain or with extremely painful disorders. Patients with sharp, stabbing pain need higher doses than patients with dull pain. Elderly adults generally require lower doses than younger adults. Neonates require relatively low doses because their blood-brain barrier is not fully developed. For all patients, dosage should be reduced as pain subsides. Outpatients should be warned not to increase dosage without consulting the prescriber.

Before an opioid is administered, respiratory rate, blood pressure, and pulse rate should be determined. The drug should be withheld and the prescriber notified if respiratory rate is at or below 12 breaths per minute, if blood pressure is significantly below the pretreatment value, or if pulse rate is significantly above or below the pretreatment value.

As a rule, opioids should be administered on a fixed schedule—not PRN. With a fixed schedule, medication is given before intense pain returns. As a result, the patient is spared needless discomfort. Furthermore, anxiety about recurrence of pain is reduced. If breakthrough pain occurs, supplemental doses of a short-acting preparation should be given.

Morphine and practically all other opioid agonists are classified under Schedule II of the Controlled Substances Act, and must be dispensed accordingly.

Routes and dosages.

Oral.

Oral dosing is generally reserved for patients with chronic, severe pain, such as that associated with cancer. Because oral morphine undergoes extensive metabolism on its first pass through the liver, oral doses are usually higher than parenteral doses. A typical dosage is 10 to 30 mg repeated every 4 hours as needed. However, oral dosing is highly individualized, and hence some patients may require 75 mg or more. Controlled-release formulations may be administered every 8 to 12 hours, and the extended-release formulation [Avinza] is given every 24 hours. Patients should be instructed to swallow these products intact, without crushing or chewing. Also, warn patients using Avinza or Embeda capsules not to drink alcohol, which can accelerate release of morphine from these products.

Intramuscular and subcutaneous.

Both routes are painful and unreliable, and hence should generally be avoided. For adults, dosing is initiated at 5 to 10 mg every 4 hours, and then adjusted up or down as needed. The usual dosage for children is 0.1 to 0.2 mg/kg repeated every 4 hours as needed.

Intravenous.

Intravenous morphine should be injected slowly (over 4 to 5 minutes). Rapid IV injection can cause severe adverse effects (profound hypotension, cardiac arrest, respiratory arrest) and should be avoided. When IV injections are made, an opioid antagonist (eg, naloxone) and facilities for respiratory support should be available. Injections should be given with the patient lying down to minimize hypotension. The usual dose for adults is 4 to 10 mg (diluted in 4 to 5 mL of sterile water for injection). The usual pediatric dose is 0.05 to 0.1 mg/kg.

Epidural and intrathecal.

When morphine is employed for spinal analgesia, epidural injection is preferred to intrathecal. With either route, onset of analgesia is rapid and the duration prolonged (up to 24 hours). The most troubling side effects are delayed respiratory depression and delayed cardiac depression. Be alert for possible late reactions. The usual adult epidural dose is 5 mg. Intrathecal doses are much smaller—about one-tenth the epidural dose.

The extended-release liposomal formulation [DepoDur], used only for postsurgical pain, is intended for epidural use only. Inadvertent intrathecal and subarachnoid administration has been associated with profound and prolonged respiratory depression, which can be managed with a naloxone infusion. Dosing is highly individualized, and must account for age, body mass, physical status, history of opioid use, risk factors for respiratory depression, and medications to be coadministered before and during surgery.

Other strong opioid agonists

In an effort to produce a strong analgesic with a low potential for respiratory depression and abuse, pharmaceutical scientists have created many new opioid analgesics. However, none of the newer pure opioid agonists can be considered truly superior to morphine: These drugs are essentially equal to morphine with respect to analgesic action, abuse liability, and the ability to cause respiratory depression. Also, to varying degrees, they all cause sedation, euphoria, constipation, urinary retention, cough suppression, hypotension, and miosis. However, despite their similarities to morphine, the newer drugs do have unique qualities. Hence one agent may be more desirable than another in a particular clinical setting. With all of the newer pure opioid agonists, toxicity can be reversed with an opioid antagonist (eg, naloxone). Important differences between morphine and the newer strong opioid analgesics are discussed below. Table 28–5 summarizes dosages, routes, and time courses for morphine and the newer agents.

TABLE 28–5

Clinical Pharmacology of Pure Opioid Agonists

		Time Course of Analgesic Effects
Drug and Route*	Equianalgesic Dose (mg)^†	Onset (min)	Peak (min)	Duration (hr)
Codeine
PO	200	30–45	60–120	4–6
IM	130	10–30	30–60	4–6
SubQ	130	10–30	30–60	4–6
Fentanyl
IM	0.1	7–8	—	1–2
IV	0.1	—	—	0.5–1
Transdermal^‡	—	Delayed	24–72	72
Transmucosal^§	—	10–15	20	1–2
Nasal spray	—	10–15	15–20	1–2
Hydrocodone
PO	30	10–30	30–60	4–6
Hydromorphone
PO (IR)	7.5	30	90–120	4
PO (ER)	7.5	—	360–480	18–24
IM	1.5	15	30–60	4–5
IV	1.5	10–15	15–30	2–3
subQ	1.5	15	30–90	4
Levorphanol
PO	4	10–60	90–120	6–8
IM	2	—	60	6–8
IV	2	—	Within 20	6–8
subQ	2	—	60–90	6–8
Meperidine
PO	300	15	60–90	2–4
IM	75	10–15	30–50	2–4
IV	75	1	5–7	2–4
subQ	75	10–15	30–50	2–4
Methadone
PO	20	30–60	90–120	4–6^¶
IM	10	10–20	60–120	4–5^¶
IV	10	—	15–30	3–4^¶
Morphine
PO (IR)	30	—	60–120	4–5
PO (ER)	30	—	420	8–12
IM	10	10–30	30–60	4–5
IV	10	—	20	4–5
subQ	10	10–30	50–90	4–5
Epidural	—	15–60	—	Up to 24
Intrathecal	—	15–60	—	Up to 24
Oxycodone
PO (IR)	20	15–30	60	3–4
PO (CR)	20	—	120–180	Up to 12
Oxymorphone
PO (IR)	10	—	—	4–6
PO (ER)	10	—	—	Up to 12
IM	1	10–15	30–90	3–6
IV	1	5–10	15–30	3–4
subQ	1	10–20	—	3–6
Rectal	10	15–30	120	3–6
Tapentadol
PO	100	45–60	90–120	4–8