23. Pain Management and Migraines - Elizabeth S. Miller, PharmD

23-1. Pain


Pain is any unpleasant sensory and emotional experience associated with actual or potential tissue damage, or defined in terms of such damage, or both. Chronic pain is a largely unrecognized problem in American society.

Currently, about 75 million individuals suffer from some form of chronic benign pain. Between one-third and one-half of chronic pain sufferers have pain severe enough to require daily medication.

Types and Clinical Presentation

Pain can be classified as acute, chronic benign, or malignant.

Acute pain is caused by an injury, illness, or surgery. It responds to medications and usually resolves when the underlying cause has been treated or healed. It is often associated with physiologic symptoms such as tachycardia, hypertension, diaphoresis, and mydriasis.

Chronic benign pain exists beyond an expected time for healing, typically 3-6 months or more. It is often associated with psychological effects, including social isolation, depression, and anxiety. Chronic pain syndromes are often not responsive to traditional analgesics and require the use of adjuvant medications.

Malignant pain may be acute, chronic, or intermittent and is often related to cancer progression or chemotherapy.

Pain is also defined by source. Such a classification divides pain into somatic, visceral, and neuropathic pain.

Somatic pain originates from the skin, muscles, tendons, ligaments, and bones. It is localized and described as sharp, stabbing, throbbing, or aching in nature. Although somatic pain can be severe, it tends to respond well to treatment with opioids.

The body's internal organs such as the liver, intestines, or stomach generate visceral pain. Visceral pain tends to be poorly localized and more likely to generate referred pain felt some distance away from the actual problem. Opioids are not as effective for visceral pain as they are for somatic pain.

Neuropathic pain results when the nerves themselves are damaged. It is typically burning in nature, although it may also be numb, be aching, or cause a sensation like an electric shock. Opioid medications are often ineffective for treating neuropathic pain, and adjuvant analgesics play a significant role in treatment.


Nociception, the pain sensation, begins when a sensory nerve ending is stimulated and sends repetitive signals to the spinal cord along ascending nerve fibers. An individual nerve does not transmit directly to the brain but instead connects to secondary nerves in the dorsal horn of the spinal cord. The secondary nerves eventually connect to nerve cells in the brain stem.

A descending antinociceptive pathway also exists. Neurotransmitters from the descending fibers inhibit the transmission of the pain signal. Opioids chemically resemble these neurotransmitters.

Chronic pain is not a prolonged version of acute pain. As pain signals are repeatedly generated, neural pathways undergo changes that make them hypersensitive to pain signals and resistant to antinociceptive input.

Diagnostic Criteria

The individual's self-report of pain is the primary source of information in acute pain.

Chronic pain assessment should include a detailed history of the pain's intensity and characteristics, a physical examination emphasizing the neurological exam, and a psychosocial assessment (

Figure 23-1).

The purpose of diagnostic tests, such as x-rays, computed tomography, or magnetic resonance imaging scans, or laboratory tests differs depending on the type of pain. In cancer patients, the major purpose of diagnostic testing is to visualize the disease progression. In chronic benign pain, the major purpose of diagnostic testing is to rule out the presence of any diseases for which there is a curative treatment.

[Figure 23-1. Algorithm for Comprehensive Evaluation and Management of Chronic Pain]

Goals of Pain Management

Acute pain

The goal in acute pain management is to provide patients with pain relief that allows them to rest comfortably and allows rehabilitation postsurgery or postinjury. This goal can be accomplished with short-acting medications administered as needed.

Malignant pain

A major goal of cancer pain management is to relieve the patient's pain without inducing disabling side effects.

The World Health Organization (WHO) has developed a three-step hierarchy for analgesic pain management in cancer pain patients (

Figure 23-2). In general, this program includes using nonopioid analgesics as a baseline, supplementing with opioid analgesics

[Figure 23-2. The WHO's Three-Step Hierarchy for Analgesic Pain Management in Cancer Patients]

as needed, and adding adjunctive medications when appropriate.

Cancer patients may suffer from constant pain that continues for months or years. For this reason, treatment with long-acting agents is more appropriate than treatment with short-acting medications. However, short-acting agents, referred to as "breakthrough" or "rescue" doses, are often available in addition to the long-acting medications.

Chronic benign pain

The goal of chronic benign pain treatment is to restore the patient to the highest degree of function possible.

Multimodal therapy, the use of several different types of treatment, is usually required. Multimodal therapies include nerve blocks, rehabilitation, physical therapy, pharmacotherapy, acupuncture, and psychotherapy. Basic pharmacotherapy follows the WHO guidelines for treating cancer pain (Figure 23-2).

Analgesics are categorized into nonopioid analgesics, opioid analgesics, and adjuvant analgesics. Nonopioid analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) relieve all types of mild to moderate pain. Unless contraindicated, all pain patients should first be given a trial of nonopioid analgesics. Nonopioids and opioids relieve pain via different mechanisms. Thus, combination therapy offers the potential for improved relief with fewer side effects. Nonopioids do not produce tolerance, physical dependence, or addiction.

Adjuvant analgesics are drugs with a primary indication other than pain. Commonly used analgesic adjuvants include antiepileptic drugs, tricyclic antidepressants, and local anesthetics.

Principles of opioid use

Opioids have no ceiling effect of analgesia.

Oral medications should be used whenever possible. Intramuscular injections are painful and should be avoided.

When patients have constant or near-constant pain, analgesics should be given around the clock. Long-acting opioid analgesics are often used for this purpose.

The use of short-acting opioids as rescue medication is controversial in chronic benign pain. If allowed, doses of rescue medications should range from 10% to 15% of the total daily long-acting opioid dose.

Mixed agonist-antagonist opioids are not used in chronic pain. They may induce a withdrawal syndrome in patients tolerant to opioids.

Drug Therapy

Mechanism of action

Morphine and other opioid agonists are thought to produce analgesia by mimicking the action of endogenous opioid peptides that bind at opioid receptors in the antinociceptive pathway.

Opioid receptors are located in the central nervous system (CNS), pituitary gland, and gastrointestinal (GI) tract. They are abundant in the periaqueductal gray matter of the brain and the dorsal horn of the spinal cord, two areas that are very active in pain reduction.

When a drug binds to one of these receptors as an agonist, it produces analgesia. When a drug binds to one of these receptors as an antagonist, analgesia and other effects are blocked.

The three major types of opioid receptor sites involved in analgesia are mu (μ), delta (δ), and kappa (κ):

• Binding to the μ receptor produces analgesia, sedation, euphoria, respiratory depression, physical dependence, constipation, and other effects.

• Activation of the κ receptor produces analgesia and respiratory depression. In addition, psychotomimetic effects such as anxiety, strange thoughts, nightmares, and hallucinations are more common.

• Activation of δ receptors produces analgesia without many adverse events. However, there is no available δ-receptor agonist.

Opioid analgesics

Opioids are classified by activity at the receptor site; that is, they are classified as pure opioid agonists, agonist-antagonists, or pure opioid antagonists.

Pure opioid agonists primarily activate μ receptors, although they may produce some κ-receptor activation (

Table 23-1). Pure opioid agonists are the most clinically useful opioid analgesics.

Morphine is the prototypical pure opioid agonist. Methadone is an opioid agonist with additional antagonist activity at the NMDA (N-methyl-D-aspartate) receptor. The NMDA receptor is believed to be active primarily in chronic pain.

Mixed agonist-antagonists bind as agonists at the κ receptor, producing weak analgesia. They bind as weak antagonists at the μ receptor (

Table 23-2). The result is more dysphoria and psychotomimetic effects with a lower risk of respiratory depression.

Pentazocine is the prototypical agonist-antagonist opioid. Buprenorphine is actually a partial agonist at

[Table 23-1. Starting Doses for Strong Opioids for Severe Pain in Adults: Mu Agonists]

μ and κ receptors. This opioid has limited efficacy in pain management and is primarily used in detoxification programs.

Opioid antagonists block the μ and κ receptors (

Table 23-3). These drugs do not produce analgesia. They are used to reverse respiratory and CNS depression caused by overdose with opioid agonists. Naloxone and naltrexone are opioid antagonists.

Opioid analgesic adverse effects

Central nervous system

Opioids produce a number of CNS effects, including sedation, euphoria, dysphoria, changes in mood, and mental clouding. Confusion, disorientation, and cognitive impairment are also possible.

Chronic sedation can be treated with CNS stimulants such as methylphenidate or dextroamphetamine. Modafinil also promotes daytime wakefulness.

Mild to moderate muscle jerks are common in patients on high doses of opioids. Myoclonus can be treated by changing the opioid dose, changing the opioid, or giving low doses of a benzodiazepine.


Morphine acts in the hypothalamus to inhibit the release of gonadotropin-releasing hormone and corticotropin-releasing factor, thus decreasing levels of luteinizing hormone, follicle-stimulating hormone, adrenocorticotropic hormone, and β-endorphins.

Changes in hormone levels may cause decreased levels of testosterone and cortisol, disturbances in menstruation, and sexual dysfunction.

High doses of morphine and related opioids produce convulsions. Most convulsions occur at doses far in excess of those required to produce analgesia.

[Table 23-2. Opioid Dosing for Mild to Moderate Pain in Adults]

[Table 23-3. Opioid Antagonists]


Respiratory depression is the most serious opioid-induced adverse effect. Opioids depress respiration by a direct effect on the brain-stem respiratory centers, making the brain stem less responsive to carbon dioxide.

The μ receptor is the primary receptor involved in respiratory depression, although activation of the κ receptor also contributes.

At equianalgesic doses, all of the pure opioid agonists depress respiration to the same degree. The agonist-antagonists have a ceiling effect (i.e., a dose beyond which no further respiratory depression or analgesia is produced), but this level is usually above recommended doses.

Opioids depress cough by inducing a direct effect on the cough reflex in the medulla.


Therapeutic doses of many opioids produce peripheral vasodilation, reduced peripheral resistance, and inhibition of the baroreceptor reflexes.

Peripheral vasodilation results primarily from opioid-induced release of histamine. Orthostatic hypotension and fainting can result. The naturally occurring and semisynthetic products are potent histamine releasers. Fentanyl has little propensity to release histamine.

Methadone has been associated with torsades de pointes, an atypical rapid ventricular tachycardia, at an average daily dose of 400 mg. Methadone should be used cautiously in patients on other QTc-prolonging medications.


All clinically significant μ agonists produce some degree of nausea and vomiting by direct stimulation of the chemoreceptor trigger zone in the medulla, sensitization of the vestibular system, and slowing of GI motility.

Nausea and vomiting commonly occur in ambulatory patients (15-40% of patients with nausea and vomiting are ambulatory). Both can be pretreated with an antiemetic such as promethazine or prochlorperazine.

Opioids promote constipation by delaying gastric emptying, slowing bowel motility, and decreasing peristalsis. Opioids may also reduce secretions from the colonic mucosa. At its worst, gastrointestinal dysfunction results in ileus, fecal impaction, and obstruction.

Because transdermal delivery bypasses absorption from the GI tract, constipation has been reported to be less frequent with this delivery method than with other methods.

Patients on opiates do not develop tolerance to constipation. All patients taking around-the-clock opioid analgesics should be placed on prophylactic bowel regimens. Bowel regimens include increased fluid and fiber intake, daily stool softeners, and mild laxatives.

Severe constipation is managed with osmotic laxatives such as magnesium citrate and milk of magnesia.


Opioids increase smooth muscle tone in the bladder and ureters and may cause bladder spasm and urgency.

An opioid-induced increase in sphincter tone can make urination difficult. Urinary retention is most common in elderly men.


Opioids increase smooth muscle tone in the biliary tract, especially in the sphincter of Oddi, which regulates the flow of bile and pancreatic fluids. This effect can result in a decrease in biliary and pancreatic secretions and a rise in the bile duct pressure. Patients may experience epigastric distress and occasionally biliary spasm.

All opioids are capable of causing constriction of the sphincter of Oddi and the biliary tract. Although morphine may cause more biliary constriction in animals than do other opioids, this finding has never been shown to be clinically useful in humans.

Skin and eye

Therapeutic doses of morphine dilate cutaneous blood vessels, which causes flushing on the face, neck, and upper thorax. Sweating and pruritus may also occur. These changes may be caused in part by release of histamine. Histamine release may induce or worsen asthmatic attacks in predisposed patients and can lead to wheezing, bronchoconstriction, and status asthmaticus.

Skin rash around the transdermal fentanyl patch is a common side effect caused by the patch adhesive.

Following a toxic dose of μ agonists, miosis is marked and pinpoint pupils are pathognomonic; however, mydriasis occurs when asphyxia intervenes.


Acute overdose with opioids is manifested by respiratory depression; somnolence progressing to stupor or coma; skeletal muscle flaccidity; cold, clammy skin; constricted pupils; and sometimes pulmonary edema, bradycardia, hypotension, and death.

An opioid antagonist may be given to block opioid receptors and reverse the effects of overdose.

Antagonist administration may cause a complete reversal of opioid effects and precipitate an acute withdrawal syndrome in persons physically dependent on opioids.

Antagonists are dosed to patient response every few minutes. If no response is observed after 10 mg, the diagnosis of opioid-induced toxicity should be questioned.

Infusion may be useful in cases of overdose with long-acting drugs such as methadone. The infusion rate for adults is approximately 100 mL/h (0.4 mg/h).

Tolerance and physical dependence

The use of opioids is often limited by concerns regarding tolerance, physical dependence, and addiction.

Tolerance can be defined as a state in which a larger dose is required to produce the same response that could formerly be elicited by a smaller dose. Tolerance to analgesia is demonstrated by the need for an increased dosage of a drug to produce the same level of analgesia. Tolerance to analgesia develops more slowly than tolerance to other opioid effects.

Tolerance to adverse effects of opioids occurs after 2-3 weeks of continuous administration. Tolerance to the constipating and neuroendocrine effects of opioids does not occur.

Physical dependence is the occurrence of a withdrawal syndrome after an opioid is stopped or quickly decreased without titration. Warn patients to avoid abrupt discontinuation of such drugs.

Addiction is the psychological dependence on the use of a substance. It is characterized by impaired control over drug use, compulsive use, craving, and continued use despite harm.

Pharmacokinetics of Selected Opioids


Compared with other opioids, morphine is relatively insoluble in lipids (i.e., in adults, only small amounts of the drug cross the blood-brain barrier).

Morphine does not accumulate in tissues when given in normal dose and therefore does not cause increasing toxicity with frequent dosing.

Morphine is primarily metabolized by glucuronidation during the first pass through the liver. Approximately 50% of morphine is converted by the liver to morphine-3-glucuronide and 15% to morphine-6-glucuronide (M6G). The pharmacologic effects of morphine (both analgesia and side effects) are in part caused by M6G.

Much of an oral dose is inactivated during this first pass through the liver; consequently, oral doses need to be much larger than parenteral doses to produce the same analgesic effects.


Fentanyl is highly soluble in lipids. It accumulates in skeletal muscle and fat and is released slowly into the blood. Plasma half-life is 3-4 hours after parenteral administration.

Fentanyl is rapidly metabolized, primarily by dealkylation, to inactive metabolites in the liver. This process is mediated through the cytochrome P450 (CYP450) 3A4 hepatic enzyme system. The presence of inactive metabolites makes fentanyl a preferred drug in patients with liver dysfunction.

Fentanyl is not used orally because of low oral bioavailability.

Transdermal fentanyl

The uptake of fentanyl through the skin is relatively slow and constant. The skin does not metabolize the drug, and 92% of the dose is delivered into the bloodstream as intact fentanyl.

Because of temperature-dependent increases in fentanyl release from the patch system as well as increased skin permeability, an increase in body temperature to 40°C (104°F) theoretically may increase serum fentanyl concentrations by approximately one-third.

Fentanyl is absorbed into the upper layers of the skin, forming a depot. Fentanyl then becomes available to systemic circulation. Serum fentanyl concentrations are measurable within 2 hours after application of the first patch, and analgesic effects can be observed 8-16 hours after application. Steady state is reached after several sequential patch applications.

Transmucosal fentanyl citrate lozenge

The absorption pharmacokinetics of fentanyl from the oral transmucosal dosage form is a combination of initial rapid absorption from buccal mucosa and delayed absorption of fentanyl from the GI tract. Normally 25% of the total dose is available by buccal absorption, and 25% is available from the GI tract, making the total bioavailability 50%.

Analgesia begins in 10-15 minutes, peaks in 20 minutes, and persists for 1-2 hours.

Transmucosal fentanyl is indicated only for those already receiving and who are tolerant to around-the-clock opioid therapy.

Fentanyl citrate buccal tablet

Following buccal administration, fentanyl is readily absorbed with an absolute bioavailability of 65%. Approximately 50% of the total dose administered is absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and undergoes more prolonged absorption from the GI tract.

Buccal tablets are indicated only for those already receiving around-the-clock opioid therapy.


After therapeutic doses, about 90% of methadone is bound to plasma protein and is widely distributed in tissues. Methadone is found in low concentrations in the blood and the brain, with higher concentrations in the kidney, spleen, liver, and lung. Terminal half-life is extremely variable (15-55 hours); therefore, accumulation is possible, and dosing intervals need to be carefully monitored.

Methadone is extensively metabolized in the liver, mainly by N-demethylation. This process appears to be mediated primarily by CYP450 3A4 and to a lesser extent by CYP450 2D6. The major metabolites are excreted in the bile and urine.

Analgesic efficacy does not correspond to the half-life of the drug. Methadone may be dosed every 3 hours for pain control.


Oxycodone is metabolized to noroxycodone, oxymorphone, and their glucuronides via the CYP450 enzyme system. The major circulating metabolite is noroxycodone. Noroxycodone is reported to be a weaker analgesic than oxycodone. Oxymorphone, although possessing good analgesic activity, is present in the plasma only in low concentrations. Its metabolism is mediated by CYP450 2D6.


Hydromorphone is metabolized to three major metabolites: hydromorphone 3-glucuronide, hydromorphone 3-glucoside, and dihydroisomorphine 6-glucoside. Whether hydromorphone is metabolized by the CYP450 system is not known. Hydromorphone is a poor inhibitor of CYP450 isoenzymes and is not expected to inhibit the metabolism of other drugs.


Normeperidine, a metabolite of meperidine, produces anxiety, tremors, myoclonus, and generalized seizures when it accumulates with repetitive dosing. Patients with compromised renal function are particularly at risk. Naloxone does not reverse this hyperexcitability. For these reasons, meperidine should not be used for more than 48 hours in patients with renal or CNS disease or at doses greater than 600 mg every 24 hours.


Propoxyphene is appropriate for short-term mild to intermittent pain. It produces a toxic metabolite, norpropoxyphene, with effects similar to normeperidine.

Drug Interactions and Drug-Disease Interactions

Drug interactions

All drugs with CNS depressant actions (barbiturates, benzodiazepines, alcohol) can intensify sedation and respiratory depression caused by morphine and other opioids.

Antihistamines, tricyclic antidepressants, and atropine-like drugs can exacerbate morphine-induced constipation and urinary retention.

Antihypertensive drugs and others that lower blood pressure can exacerbate opioid-induced hypotension.

The combination of meperidine and a monoamine oxidase (MAO) inhibitor has produced a syndrome characterized by excitation, delirium, hyperpyrexia, convulsions, and severe respiratory depression. Death has also occurred. Although this syndrome has not been reported with other opioids, combinations containing opioids and MAO inhibitors should be avoided.

Agonist-antagonists can precipitate a withdrawal syndrome if administered to an individual who is physically dependent on a pure opioid agonist.

CYP450 enzymes metabolize codeine, hydrocodone, fentanyl, methadone, and oxycodone. Although not well documented, drug interactions through this system may exist. In particular, transdermal fentanyl should be used with caution in a patient on a CYP450 3A4 inhibitor. The patient should be monitored over an extended period and dose adjustments made as appropriate.

Codeine, hydrocodone, and oxycodone require metabolism through CYP450 2D6 to active drug (

Table 23-4). Approximately 7% of Caucasians, 3% of African Americans, and 1% of Asians are poor metabolizers of CYP450 2D6; they produce no CYP450 2D6 or produce undetectable levels of it. Poor metabolizers may experience little or no analgesia from drugs requiring 2D6 for conversion to active metabolites.

About 5% of the patients have multiple copies of the CYP450 2D6 gene, making them ultrafast metabolizers. The clearance of some opioids may be increased, making more frequent dosing of the medications necessary.

[Table 23-4. CYP450 2D6 Enzyme Activity]

Drug-disease interactions

In view of the extensive hepatic metabolism of opioids, their effects may be increased in patients with liver disease, particularly those with severe liver failure. Most opioids require dose reduction in severe liver disease.

Fentanyl, morphine, and methadone require dosing adjustment in renal impairment. Doses of fentanyl and morphine should be reduced 25% when creatinine clearance (CrCl) is 10-50 mL/min and by 50% when CrCl is < 10 mL/min. The dosing interval of methadone should be increased to at least every 6 hours when CrCl is 10-50 mL/min and to every 8 hours when CrCl is < 10 mL/min.

Renal impairment slows the clearance of morphine conjugates, resulting in accumulation of the active metabolite M6G. For this reason, dosage reduction may be advisable in the presence of clinically significant renal impairment.

Methadone appears to be firmly bound to protein in various tissues, including the brain. After repeated administrations, methadone gradually accumulates in tissues. The risk of accumulation is greater in patients with impaired renal or hepatic function because both organs are involved in the metabolism of methadone.

Patient Counseling

Respiratory depression is increased by concurrent use of other drugs with CNS-depressant activity (e.g., alcohol, barbiturates, and benzodiazepines). Outpatients should be warned against the use of alcohol with all other CNS depressants.

Inform patients about symptoms of hypotension (lightheadedness, dizziness). Patients should minimize hypotension by moving slowly when changing from a supine to an upright position.

Fentanyl transdermal patch

The fentanyl transdermal patch must be applied to a clean, nonhairy site on the upper torso. Only water should be used to clean the area. Soap or alcohol can increase the effects of the medication and should not be used. The patch should not be applied to oily, broken, burned, cut, or irritated skin. It must be held in place for a minimum of 30 seconds to ensure adhesion.

Each new patch should be applied to a different area of skin to avoid irritation. If a patch comes off or causes irritation, it should be removed and a new patch applied to a different site.

To dispose of the patch, fold it in half and flush down the toilet.

Do not cut or damage the patch.

Temperature-dependent increases in fentanyl release from the patch could result in an overdose. Advise patients to avoid exposing the patch to direct external heat sources such as heating pads, electric blankets, heat lamps, saunas, hot tubs, and heated waterbeds. In addition, patients who develop a high fever while wearing the patch should contact their physician immediately.

Long-acting opioid formulations

The long-acting formulations should be swallowed whole (i.e., not broken, chewed, or crushed).

Avinza, a long-acting morphine capsule formulation, contains fumaric acid. Doses above 1,600 mg per day contain a quantity of fumaric acid that has not been demonstrated to be safe and may result in serious renal toxicity.

Kadian and Avinza (long-acting morphine sulfate) may be opened and the beads ingested with a small amount of applesauce (sprinkle administration). In addition, Kadian is approved for sprinkle administration through a gastrostomy tube.

Patients must not consume alcoholic beverages or any medications containing alcohol while on Opana ER therapy. The co-ingestion of alcohol with Opana ER may result in increased plasma levels and a potentially fatal overdose of oxymorphone. In addition, food increases the Opana ER maximum concentration by approximately 50%. Opana ER should be ingested 1 hour before and 2 hours after a meal.

Transmucosal fentanyl citrate lozenge

The lozenge is used by placing it in the mouth between the cheek and the gum. Consumption of the lozenge should take 15 minutes. Another lozenge may be used 30 minutes after the start of the first one. Tell the patient not to bite or chew the lozenge.

To dispose of a finished lozenge, discard the handle in a place that is out of reach of children and pets. If medicine remains on the handle, place the handle under hot running tap water until the medicine is dissolved. Never leave unused or partly used lozenges where children or pets can get to them.

Fentanyl citrate buccal tablet

Once removed from the blister pack, the lozenge must be used right away. It is placed in the mouth above the back molars and between the upper cheek and gum. It is left in place until it dissolves, which may take between 14 and 25 minutes. After 30 minutes, any remaining tablet is swallowed with a glass of water.

Parameters to monitor

Evaluate for pain control 1 hour after opioid administration. If analgesia is insufficient, consider a dosage increase. Patients taking opioids chronically should be evaluated regularly for adequate doses.

Monitor the patient for respiratory depression. Higher risk for respiratory depression exists in patients who are not tolerant to opioid analgesics. Consider treatment when the respiratory rate is less than 8-12 respirations per minute for 30 minutes or longer despite stimulation or if oxygen saturation is less than 90%.

If a patient is easily arousable, he or she is unlikely to have respiratory depression.


Tramadol is an analogue of codeine, whose mechanism of action is not completely understood. Analgesia is apparently mediated by binding of the parent molecule and the O-desmethyltramadol (M1) active metabolite to μ opioid receptors, as well as by weak inhibition of neuronal uptake of norepinephrine and serotonin. Tramadol is not a federally controlled substance.

The liver extensively metabolizes tramadol. The formation of the M1 active metabolite is dependent on CYP450 2D6. M1 appears to be up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in binding to μ opioid receptors. CYP450 3A4 and CYP450 2B6 also play a role in tramadol metabolism. Caution should be exercised when administering tramadol to patients on CYP450 2D6 and CYP450 3A4 inhibitors.

The most common adverse effects are sedation, dizziness, headache, dry mouth, and constipation. Respiratory depression is minimal. Seizures have been reported; avoid use of tramadol in patients with seizure disorders or recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, and CNS infections).

23-2. Nonpharmacologic Treatment of Pain

General Principles of Nonpharmacologic Treatment

Nonpharmacologic strategies used in combination with appropriate drug regimens may improve pain relief by enhancing the therapeutic effects of medications and permitting use of lower doses.

Nonpharmacologic interventions should not be a substitute for analgesic use.

Physical Interventions

Physical therapy

Physical therapy is most commonly used to help restore physical strength and functioning after injury or surgery.

Physical therapy can provide pain relief for patients with musculoskeletal pain, some types of neuropathic pain, and sympathetically mediated pain.


The National Institutes of Health recognize the benefit of acupuncture as an adjunct treatment of painful conditions.

Transcutaneous electrical nerve stimulation

In transcutaneous electrical nerve stimulation (TENS), a controlled, low-voltage electrical current is applied through electrodes placed on the skin. Theoretically, the current will interfere with the ability of nerves to transmit pain signals to the spinal cord and brain. After several decades of research, it still is not clear if TENS provides any better pain relief than placebo.


Neurostimulation involves implanting a computerized generator and electrodes near the spinal cord, near the peripheral nerves, or within the brain. Stimulators are most effective for patients with neuropathic pain and are not very beneficial in other types of pain.

Behavioral Techniques


In biofeedback, electrodes connected to amplifiers are placed on the body or scalp. During biofeedback sessions, a therapist helps the patient learn to mentally control and change the signals from the electrodes, which helps the patient gain conscious control over normally unconscious functions. Biofeedback is most commonly used to relax muscles and reduce stress. Its advantages are that it is noninvasive, inexpensive, and safe; however, usually between 5 and 15 sessions are required before effective control is achieved.

Distraction and relaxation

Distraction and relaxation assist the patient in refocusing attention on nonpainful stimuli. Both are believed to improve mental health, which translates into improved pain control.

23-3. Migraine


Migraine is a chronic neurovascular disorder characterized by recurrent attacks of severe headache and autonomic nervous system dysfunction. Some patients also experience aura with neurologic symptoms. An estimated 18% of women and 6% of men experience migraine.

Clinical Presentation and Diagnostic Criteria

Migraine classification is based on whether an aura of visual or sensory symptoms is present. Migraine with aura is less common than migraine without aura.

Migraine headache manifests as moderate or severe throbbing pain that is localized in the temple or around the eye. It is accompanied by nausea in 90% of patients and vomiting in about half of patients.

Photophobia (increased sensitivity to light) and phonophobia (increased sensitivity to sound) also are frequent complaints. A prodrome of mood changes, stiff neck, fatigue, or other symptoms may occur hours or days before the onset of the headache.

Criteria for diagnosing migraine without aura

• The patient has at least five headaches lasting 4-72 hours each.

• The headaches have at least two of the following four characteristics:

• Unilateral location

• Pulsating quality

• Moderate or severe intensity (inhibits or prohibits daily activities)

• Aggravation with walking stairs or similar routine physical activity

• During the headache, at least one of the following symptoms occurs:

• Nausea or vomiting

• Photophobia

• Phonophobia

• Symptoms cannot be consistent with other headache types.

Criteria for diagnosis of migraine with aura

• The patient has at least two attacks with three of the following four criteria:

• One or more completely reversible aura symptoms occur, indicating focal cerebral cortical or brain stem dysfunction (or both).

• At least one aura symptom develops gradually (> 4 minutes) or two or more symptoms occur in succession.

• No aura symptom lasts > 60 minutes.

• Headache follows aura in < 1 hour.

• There is no evidence of related organic disease.


Migraine and the brain

The pathogenesis of migraine is unclear and is thought to be multifactorial. The current thinking is that a primary neuronal dysfunction originates in the CNS, leading to a sequence of changes that account for the different stages of migraine.

The Cortical Spreading Depression theory explains that a wave of depolarization spreads across the cerebral cortex from occipital to frontal regions, resulting in brain ion dysfunction and secondary vasoconstrictor vascular events. These changes account for the progression and variety of symptoms that occur in patients with prodromal or aura phase.

The headache phase is probably related to trigeminovascular activation with the release of inflammatory neuropeptides, such as substance P, neurokinin A, and calcitonin gene-related peptide, in the trigeminal vascular system. This process, in turn, causes vasodilation.

It is suggested that the pain of headache is due to vasodilation as well as direct stimulation via the thalamus of the cortical pain areas situated in higher centers of the CNS. Not all migraine patients experience aura, so both direct effects and the secondary vasoactive responses account for the headache in patients who have migraine attacks without the aura.

The pathophysiology of the postdrome is unknown, but it may be caused by a gradual recovery from the extreme neurologic disruption that occurs during migraine.

Individuals prone to migraine may have a genetic migraine threshold that renders them susceptible to a migraine attack on exposure to some or any of a range of patient-specific triggers. Hormonal influences, environmental and physiologic stressors, low blood sugar, and fatigue are all thought to affect this threshold. Once the threshold is exceeded, trigeminovascular activation is thought to be responsible for inducing a migraine.

Treatment Principles

Abortive therapy

The U.S. Headache Consortium identifies the following goals for successful treatment of acute attacks of migraine:

• Treat attacks rapidly and consistently and prevent recurrence.

• Restore the patient's ability to function.

• Minimize the use of rescue medication.

• Optimize self-care and reduce subsequent use of resources.

• Promote cost-effective therapies with minimal adverse effects.

Successful treatment of migraine depends on early intervention in relation to onset of headache and adequate dosing.

Preventive therapy

Preventive therapy should be considered in the following situations:

• Attacks unresponsive to abortive medication

• Attacks causing substantial disability

• Attacks occurring twice or more monthly

• Patient at risk for rebound headache

• Trend in increasing frequency of attacks

Two-thirds of patients taking preventive medication will have a 50% decrease in the frequency of attacks.

The minimum duration of trial for a daily preventive medication is 2-3 months. No consensus exists on the duration of the prophylaxis trial period; however, prophylaxis efficacy may continue to improve when a medication is taken continuously for months to years.

The goals of migraine preventive therapy are as follows:

• Reduce attack frequency, severity, and duration.

• Improve responsiveness to treatment of acute attacks.

• Improve function and reduce disability.

Rebound headaches

Persons who take abortive medications daily can develop drug rebound headaches, or headaches that begin upon discontinuation of a medication. Essentially all of the medications, with the possible exception of the triptans, cause rebound headache.

Drug Therapy

Abortive therapy: Nonprescription medications

Aspirin, acetaminophen, ibuprofen, and other aspirinlike analgesics provide adequate relief of mild to moderate migraines. Advil Migraine (ibuprofen 200 mg liquid-filled caps) and Motrin Migraine Relief (ibuprofen 200 mg) are examples of nonprescription medications indicated for migraine relief.

Combination products containing aspirin, acetaminophen, or both with caffeine are also available without a prescription. Caffeine has analgesic and possibly anti-inflammatory properties. It may also increase gastric acidity and perfusion, enhancing the absorption of aspirin. Excedrin Migraine (acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg) is an example of an available combination nonprescription product.

Abortive therapy: Nonspecific prescription medications

Combination products containing an analgesic, caffeine, and butalbital or codeine are available. The butalbital may be useful for its sedative properties. Excessive use of these products can cause physical dependence and rebound headaches.

A combination of the vasoconstrictor isometheptene, the sedative dichloralphenazone, and acetaminophen (Midrin) may be useful for mild to moderate migraines. Isometheptene is also available in combination with acetaminophen and caffeine (Migraten). Both combinations are generally well tolerated.

Opioids are well recognized as good analgesics, but strong evidence exists only for the efficacy of butorphanol nasal spray for migraine. Although opioids are commonly used, surprisingly few studies of opioid use in headache pain document whether overuse and the development of dependence are as frequent as clinically perceived.

Given intravenously, the antiemetic metoclopramide may be appropriate as monotherapy for acute attacks, particularly in patients with significant nausea. Chlorpromazine and prochlorperazine may also be considered. Serotonin-receptor antagonists (5-HT3) have not been shown to be useful migraine treatments.

Abortive therapy: Ergotamine

Mechanism of action

In cranial arteries, ergotamine acts directly to promote constriction and reduce the amplitude of pulsations. In addition, the drug can affect blood flow by depressing the vasomotor center. Antimigraine effects are possibly due to agonist activity at serotonin receptor subtypes 5-HT1B and 5-HT1D.

Because of the risk of dependence, ergotamine should not be taken daily on a long-term basis.

Caffeine may be added to ergotamine to enhance vasoconstriction and ergotamine absorption (

Table 23-5).


Oral ergotamine has poor bioavailability because of extensive first-pass metabolism. Sublingual administration may not provide therapeutic blood levels.

Although the half-life of ergotamine is only 2 hours, pharmacologic effects can be seen for 24 hours after administration.

The drug is eliminated primarily by hepatic metabolism. Metabolites are excreted in the bile.

Adverse effects

Ergotamine is well tolerated at usual therapeutic doses.

The drug can stimulate the chemoreceptor trigger zone to cause nausea and vomiting in about 10% of patients. Concurrent treatment with metoclopramide or a phenothiazine antiemetic can help suppress this response.

Other common side effects include weakness in the legs, myalgia, numbness and tingling in the periphery, angina-like pain, tachycardia, and bradycardia.


Acute or chronic overdose can cause serious toxicity (ergotism). Symptoms include ischemia, myalgias, and paresthesias. Ischemia can progress to gangrene.

The risk of ergotism is highest in patients with sepsis, peripheral vascular disease, and renal or hepatic impairment.

Drug-drug and drug-disease interactions

Ergotamine should not be combined with selective serotonin-receptor agonists because of the risk of a prolonged vasospastic reaction.

[Table 23-5. Agents Used in Migraine Treatment]

Separate doses of ergotamine and serotonin agonists by at least 24 hours.

Ergotamine is contraindicated for patients with hepatic or renal impairment, sepsis, coronary artery disease (CAD), and peripheral vascular disease.

Patient counseling

Monitor patients to avoid overuse of the medication.

Ergotamine and its derivatives are U.S. Food and Drug Administration (FDA) pregnancy category X. They should not be taken during pregnancy because of their ability to promote uterine contractions and cause fetal harm or abortion.

Teach patients to recognize signs of ergotism. Muscle pain, paresthesias, and cold or pale extremities should be reported immediately.

Abortive therapy: Dihydroergotamine

Mechanism of action

The action of dihydroergotamine (DHE) is similar to that of ergotamine. Like ergotamine, DHE alters transmission at serotonergic, dopaminergic, and α-adrenergic junctions.

In contrast to ergotamine, DHE causes minimal peripheral vasoconstriction, little nausea and vomiting, and no physical dependence. However, diarrhea is prominent.

Contraindications are the same as for ergotamine: CAD, peripheral vascular disease, sepsis, pregnancy, and hepatic or renal impairment.

As with ergotamine, do not administer DHE within 24 hours of a serotonin agonist.


DHE is not active orally because of extensive first-pass metabolism.

An active metabolite, 8´-hydroxydihydroergotamine, contributes to its therapeutic effects. The half-life of DHE plus its active metabolite is about 21 hours.

Concomitant administration of DHE with potent CYP450 3A4 inhibitors, including protease inhibitors and macrolide antibiotics, is contraindicated. Because CYP450 3A4 inhibition elevates the serum levels of DHE, the risk for vasospasm leading to cerebral ischemia or ischemia of the extremities is increased.

Abortive therapy: Selective serotonin-receptor agonists

The selective serotonin-receptor agonists, also known as triptans, are first-line drugs for terminating a migraine attack (

Table 23-6). The triptans all activate 5-HT1B/5-HT1D and to a lesser extent 5-HT1A or 5-HT1F receptors. Triptans have no known affinity for 5-HT2 or 5-HT3 and other 5-HT receptor subclasses,

[Table 23-6. Selective Serotonin Receptor Agonists (Triptans)]

nor do they bind to adrenergic, dopaminergic, muscarinergic, or histaminergic receptors.


The pharmacokinetics of the different triptans vary somewhat. However, all are generally well tolerated and efficacious at appropriate doses.

Subcutaneous sumatriptan injection has the fastest onset of action when compared with other triptans. Sumatriptan nasal spray has a slightly slower onset than the injection.

The onset of the majority of oral triptans, including the dissolving wafers, is similar among the available agents. Rizatriptan may have a slightly faster onset of action at 1.0-1.5 hours.

Migraine recurrence rates may be lower with long-half-life triptans such as naratriptan and frovatriptan. However, triptans with longer half-lives tend to have a slower onset of action.

Adverse effects

Triptans are generally well tolerated. Most side effects are mild and transient.

The triptans differ slightly from one another in terms of tolerability but not in terms of safety.

The most frequent side effects are (1) tingling and paresthesias and (2) sensations of warmth in the head, neck, chest, and limbs. Less frequent effects are dizziness, flushing, and neck pain or stiffness.

Chest symptoms

About 50% of patients on sumatriptan experience unpleasant chest symptoms usually described as "heavy arms" or "chest pressure" rather than pain. These symptoms are transient and not related to ischemic heart disease. Possible causes are pulmonary vasoconstriction, esophageal spasm, intercostal muscle spasm, and bronchoconstriction.

Coronary vasospasm

Rarely, sumatriptan causes angina secondary to coronary vasospasm. Electrocardiographic changes have been observed in patients with CAD or Prinzmetal's (vasospastic) angina.

To reduce the risk of angina, do not give sumatriptan to patients who have risk factors for CAD. These patients include postmenopausal women, men over 40, smokers, and patients with hypertension, hypercholesterolemia, obesity, diabetes, or a family history of CAD.

Other adverse effects

Mild reactions include vertigo, malaise, fatigue, and tingling sensations.

Transient pain and redness may occur at sites of subcutaneous injection.

Intranasal administration may cause irritation in the nose and throat as well as an offensive or unusual taste.

Drug-drug and drug-disease interactions

All triptans and ergot alkaloids cause vasoconstriction. Accordingly, if one triptan is combined with another or with an ergot alkaloid, excessive and prolonged vasospasm could result.

Do not use triptans within 24 hours of an ergot derivative or another triptan.

MAO inhibitors can suppress degradation of triptans, which causes plasma levels to rise and results in toxicity. Furthermore, triptans should not be administered within 2 weeks of stopping an MAO inhibitor.

Triptans are contraindicated for patients with a history of ischemic heart disease, myocardial infarction, uncontrolled hypertension, or other heart disease. Do not use triptans during pregnancy.

Patient counseling

Patients should be counseled to contact a physician if pain or tightness in the chest occurs.

Patients should not exceed daily maximum doses. If migraines occur more than three times a month, prophylactic treatment should be considered.

Pain at the sumatriptan injection site should last less than 1 hour.

Migraine Prophylactic Therapy

Table 23-7 summarizes selected migraine preventive treatments.

β-adrenergic blocking agents

Propranolol is one of the drugs of choice for migraine prophylaxis. This agent can reduce the number and intensity of attacks in about 70% of patients.

Not all β-blockers are active against migraines. Recommended first-line agents include propranolol and timolol. Additional agents with demonstrated efficacy include atenolol and metoprolol.

Because not all β-blockers are effective, a mechanism other than β-blockade is apparently responsible for the beneficial effects.


Good evidence supports the efficacy of divalproex sodium and sodium valproate. Adverse events with these therapies include weight gain, hair loss, tremor,

[Table 23-7. Selected Migraine Preventive Treatments]

and teratogenic potential, such as neural tube defects. Both are considered first line for prevention.

Topiramate has good scientific evidence for clinical efficacy. It is FDA approved for migraine prevention. Side effects associated with use include paresthesia, fatigue, nausea, dizziness, and difficulty concentrating. Anorexia and weight loss may also occur.

Limited evidence indicates moderate efficacy of gabapentin. Gabapentin has no documented drug interactions and is excreted unchanged in the urine. Drowsiness and dizziness are common adverse events.


Amitriptyline has been more frequently studied than the other antidepressants and is the only one with consistent support for efficacy in migraine prevention. It is considered a first-line treatment. There is limited evidence for the use of other tricyclic antidepressants (TCAs) such as nortriptyline, protriptyline, doxepin, clomipramine, or imipramine.

Drowsiness, weight gain, and anticholinergic symptoms are frequently reported with the TCAs.

Limited evidence exists that supports using fluoxetine at dosages ranging from 20 mg every other day to 40 mg per day. Although benefit may be seen in clinical practice, controlled trials offer no evidence for the use of fluvoxamine, paroxetine, sertraline, bupropion, mirtazapine, trazodone, or venlafaxine in this manner.

Calcium channel blockers

Several calcium channel blockers are moderately effective at reducing migraine attacks. They include verapamil and diltiazem. Beneficial effects develop slowly, reaching a maximum in 1-2 months.

Calcium channel blockers cause side effects in 20-60% of patients. Constipation and orthostatic hypotension are most common. Peripheral edema may occur as well.

Cardiovascular effects, including bradycardia, arrhythmias, QT prolongation, may necessitate appropriate monitoring.


Methysergide is an ergot alkaloid used in migraine prophylaxis. It is not effective for aborting an ongoing attack.

It is more efficacious than propranolol but has significantly more side effects.

The drug seems to activate serotonin receptors in the CNS. Suppression of pain pathways by this mechanism may explain its usefulness.

Methysergide causes a number of adverse effects. With long-term therapy, methysergide can cause retroperitoneal, pleuropulmonary, and cardiac fibrosis. Fibrotic changes, although rare, are most serious.

Other adverse effects include vascular insufficiency, insomnia, altered mood, depersonalization, hallucinations, nightmares, and GI disturbances such as nausea, vomiting, and diarrhea.

Ergot alkaloids, serotonin-receptor agonists, β-adrenergic blockers, dopamine, and drugs that inhibit the CYP450 3A4 subclass of hepatic metabolizing enzymes increase the risk of arterial spasm.

23-4. Nonpharmacologic Treatment of Migraines

General Principles of Nonpharmacologic Therapies

Nonpharmacologic approaches may be well suited to patients who have exhibited a poor tolerance or poor response to drug therapy; who have a contraindication to drug therapy; or who have a history of long-term, frequent, or excessive use of analgesics or other acute medications. Nonpharmacologic interventions may also be useful in patients who are pregnant, are planning to become pregnant, or are nursing.

Treatment Recommendations

Patients with migraine pain may experience relief by resting or sleeping in a cool, quiet, dark environment.

Half of migraine patients experience considerable relief by applying a cold compress to the head.

Relaxation training, thermal biofeedback combined with relaxation training, electromyographic biofeedback, and cognitive-behavioral therapies are somewhat effective in preventing migraine.

Evidence pertaining to the treatment of migraine with acupuncture is limited, and the results are mixed. Similarly, limited evaluation has been conducted with hypnosis, TENS, cervical manipulation, and hyperbaric oxygen.

Trigger Management

Trigger management is important in preventing migraine attacks. Triggering factors can cause migraine and if, recognized and avoided, may impede an impending attack.

Triggers vary from person to person. Examples of triggers include changes in weather or air pressure; bright sunlight, glare, or fluorescent lights; chemical fumes; menstrual cycles; and certain foods such as processed meats, red wine, beer, dried fish, broad beans, fermented cheeses, aspartame, and monosodium glutamate.

23-5. Key Points

Pain Management

• Opioids relieve pain by mimicking the actions of endogenous opioid peptides at μ, δ, and κ receptors.

• Opioids fall into three categories: pure μ agonists, agonist-antagonists, and pure antagonists. Pure μ agonists are the most pharmacologically useful.

• Addiction is a behavior pattern involving the continued use of a substance for nonmedical reasons despite harm. Physical dependence refers to the occurrence of an abstinence syndrome if the opioid is abruptly discontinued.

• With prolonged use, tolerance develops to analgesia, euphoria, sedation, respiratory depression, and other adverse effects—but not to constipation.

• Opioid overdose induces coma, respiratory depression, and pinpoint pupils. Naloxone and other pure opioid antagonists are used in cases of overdose to reverse most effects of opioids.

• Alcohol and other CNS depressants can intensify opioid-induced sedation and respiratory depression. TCAs and antihistamines may worsen opioid-induced constipation and urinary retention.

• Hydrocodone, codeine, fentanyl, methadone, and oxycodone are metabolized by the CYP450 system. Thus, drug interactions through the CYP450 enzymes may exist.

• The liver extensively metabolizes opioids; dose adjustments may be required in liver dysfunction. Fentanyl, morphine, and methadone require dosing adjustments in renal dysfunction.


• The pathogenesis of migraine is unclear and is thought to be multifactorial. The current thinking is that a primary neuronal dysfunction originates in the CNS, leading to a sequence of changes that account for the different stages of migraine.

• The goal of abortive therapy is to eliminate headache pain and associated nausea and vomiting. The goal of preventive therapy is to reduce the incidence of migraine attacks.

• Nonopioid analgesics are effective for abortive therapy of mild to moderate pain.

• Opioid analgesics are reserved for severe migraine that has not responded to other drugs.

• Ergotamine is used for abortive therapy but should not be used daily. Overdose with ergotamine can cause ergotism, a serious condition in which generalized constriction of peripheral arteries and arterioles causes severe tissue ischemia.

• Triptans are drugs of choice for abortive therapy of migraines. They activate 5-HT1B/5-HT1D receptors, thereby causing constriction of cranial blood vessels and suppression of inflammatory neuropeptides.

• Triptans can cause coronary vasospasm and are contraindicated in patients with ischemic heart disease, prior myocardial infarction, and uncontrolled hypertension. If a triptan is combined with another triptan or with an ergot alkaloid, excessive prolonged vasospasms could result. Because of increased triptan toxicity, triptans should not be administered concurrently with MAO inhibitors and should not be given within 2 weeks of stopping an MAO inhibitor.

• The most recently published clinical practice guidelines consider propranolol, amitriptyline, divalproex sodium, and timolol first line for prevention of migraines. Since the publication of the guidelines, topiramate has gained an FDA indication for migraine prevention.

23-6. Questions


Approximately how many people in the United States experience severe chronic pain?

A. 10 million

B. 23 million

C. 40 million

D. 50 million

E. 75 million



Addiction is currently understood to be

I. characterized by compulsive use of drugs.

II. synonymous with physical dependence on a medication.

III. the use of a substance for psychic effects.

A. I only

B. III only

C. I and III only

D. II and III only

E. I, II, and III



The World Health Organization analgesic hierarchy emphasizes

A. concurrent use of nonopioids, opioids, and adjuvant medications.

B. avoiding opioid use.

C. reserving opioid use only for severe pain.

D. using single agents rather than a combination of medications.

E. using nonopioids only for treatment of mild pain.



All of the following adverse effects are manifestations of μ opioid agonists except

A. constipation.

B. respiratory depression.

C. atrial flutter.

D. nausea.

E. miosis.



The preferred route of opioid administration is

A. oral.

B. intravenous.

C. subcutaneous.

D. rectal.

E. intramuscular.



Which of the following opioids has the longest duration of analgesic effect?

A. Methadone

B. Controlled-release morphine

C. Hydromorphone

D. Transdermal fentanyl

E. Controlled-release oxycodone



All of the following opioids are metabolized through the cytochrome P450 hepatic enzyme system except

A. hydrocodone.

B. oxycodone.

C. morphine.

D. methadone.

E. fentanyl.



The clearance of which opioid may be increased in patients with multiple copies of the CYP450 2D6 gene?

A. Methadone

B. Oxycodone

C. Fentanyl

D. Morphine

E. Hydromorphone



Which of the following statements regarding methadone pharmacokinetics is true?

A. The half-life corresponds to analgesic efficacy.

B. It is highly plasma protein bound and widely distributed in tissue.

C. The clearance of methadone is rapid, resulting in frequent dosing.

D. Methadone has low bioavailability from the GI tract and therefore is not useful when given orally.

E. Methadone is metabolized by hepatic glucuronidation.



Which agent can be used to reverse respiratory effects caused by opioid overdose?

A. Naloxone

B. Pentazocine

C. Buprenorphine

D. Naltrexone

E. Tramadol



Which of the following opioids is not appropriate for use as an around-the-clock medication in chronic pain?

A. Morphine

B. Oxycodone

C. Fentanyl

D. Hydromorphone

E. Methadone



Which of the following opioids has a toxic metabolite that can accumulate in renal dysfunction?

A. Oxycodone

B. Fentanyl

C. Meperidine

D. Hydromorphone

E. Methadone


Use Case Study 1 to answer questions 13 and 14.

Case Study 1


Patient name: Mary Martin

Age: 65

Address: 815 Elm Street

Sex: Female

Allergies: NKDA


Chronic low back pain



Chronic constipation




Paxil 20 mg qd


Zocor 40 mg qd


Lotensin 20 mg qd


Premarin 0.625 mg


Morphine sulfate extended-release 60 mg bid


Senokot S


Elavil 50 mg qhs


Milk of magnesia


Which of Mrs. Martin's medications is most likely to worsen opioid-induced constipation?

A. Paxil

B. Zocor

C. Lotensin

D. Premarin

E. Elavil



The physician recommends changing Mrs. Martin's opioid to one that is less constipating. Which of the following medications is least likely to cause constipation?

A. Morphine extended release

B. Methadone

C. Oxycodone extended release

D. Transdermal fentanyl patch

E. Hydromorphone



The rationale of adding caffeine to a simple analgesic for migraine treatment is to

I. decrease the required dose of acetaminophen and aspirin.

II. cause cerebral arterial vasoconstriction.

III. increase gastric acidity and perfusion, enhancing aspirin absorption.

A. I only

B. III only

C. I and III only

D. II and III only

E. I, II, and III



Which of the following agents is a selective serotonin agonist?

A. Sumatriptan

B. Ketorolac

C. Dihydroergotamine

D. Metoclopramide

E. Caffeine



Which is true regarding the adverse effects of ergotamine?

A. Ergotamine inhibits the chemoreceptor trigger zone to minimize nausea and vomiting.

B. Ergotamine has minimal risk of dependence.

C. Muscle weakness is an uncommon side effect of ergotamine.

D. Angina-like pain reported with the triptans is not seen with ergotamine use.

E. Overuse of ergotamine can result in ischemia.



Which statement about triptans is correct?

A. Few contraindications exist to the use of triptans.

B. Triptans are contraindicated in ischemic cardiovascular disease.

C. Triptans are preferred for migraine treatment during pregnancy.

D. Patients taking ergot alkaloids can use triptans concomitantly.

E. Triptans are strictly contraindicated in patients with hypertension.



Which of the following statements is true regarding the use of opioids for migraines?

A. Opioid use is not associated with rebound headaches.

B. Butorphanol nasal spray is efficacious in migraine abortive therapy.

C. Opioids in combination with butalbital and caffeine do not produce physical dependence.

D. Opioids scheduled around the clock are useful for migraine prophylaxis.

E. Opioids are not commonly prescribed for migraine treatment.



Which of the following agents is most likely to cause pulmonary fibrosis?

A. Methysergide

B. Amitriptyline

C. Carbamazepine

D. Propranolol

E. Valproic acid



Which statement about Midrin is correct?

I. Midrin can be used concomitantly with over-the-counter products containing acetaminophen.

II. Midrin dose is limited to 5 capsules per 12 hours.

III. Midrin may cause sedation.

A. I only

B. III only

C. I and III only

D. II and III only

E. I, II, and III



Dihydroergotamine differs from ergotamine in which of the following ways?

A. DHE has higher incidence of nausea and vomiting.

B. DHE has higher incidence of physical dependence.

C. DHE has no contraindications for ischemic cardiovascular disease.

D. DHE has a higher incidence of diarrhea.

E. DHE can be administered concomitantly with a triptan.


Use Case Study 2 to answer questions 23 and 24.

Case Study 2


Patient name: James Hunt

Age: 45

Allergies: NKDA

Address: 817 Elm Street

Sex: Male

Diagnosis: Migraine with aura, controlled hypertension







Sumatriptan 100 mg tablet

Oral, use as directed

#9 tabs


Lisinopril 10 mg tablet

Oral, qd

#30 tabs


Sumatriptan 100 mg tablet

Oral, use as directed

#9 tabs


Lisinopril 10 mg tablet

Oral, qd

#30 tabs


Sumatriptan 100 mg tablet

Oral, use as directed

#9 tabs


Lisinopril 10 mg tablet

Oral, qd

#30 tabs


Sumatriptan 100 mg tablet

Oral, use as directed

#9 tabs


Sumatriptan 100 mg tablet

Oral, use as directed

#9 tabs


Which of the following statements is true regarding initiation of prophylactic migraine therapy in Mr. Hunt?

A. Mr. Hunt is at high risk for rebound headaches caused by excessive sumatriptan use.

B. Mr. Hunt is limiting his sumatriptan use to 3 days per week and is not a candidate for prophylactic treatment.

C. Mr. Hunt is a candidate for prophylactic therapy because of the increasing frequency of attacks.

D. Mr. Hunt requires prophylactic therapy because his hypertension is a contraindication to using abortive therapies.

E. Prophylactic treatment is contraindicated in migraines with aura.



Which medication is appropriate to give Mr. Hunt for migraine prophylaxis?

A. Butorphanol

B. Propranolol

C. Dihydroergotamine

D. Acetaminophen

E. Hydrocodone


23-7. Answers


E. Currently, about 75 million individuals suffer from some form of chronic benign pain.



C. Physical dependence is the occurrence of a withdrawal syndrome after an opioid is stopped or quickly decreased without titration. Addiction is the psychological dependence on the use of substances for psychic effects and is characterized by compulsive use.



A. The WHO analgesic hierarchy involves choosing among three stepped levels of treatment. Mild pain may respond to nonopioid drugs alone. Combining a low-dose opioid with a nonopioid can relieve pain of moderate severity. More severe pain requires the addition of a higher-dose opioid preparation to the nonopioid. At any step, analgesic adjuvants may be useful.



C. Atrial flutter is not a documented adverse effect of opioids. However, therapeutic doses of many opioids produce peripheral vasodilation, reduced peripheral resistance, and inhibition of the baroreceptor reflexes. Recently, methadone has been associated with torsades de pointes, an atypical rapid ventricular tachycardia.



A. Oral medications should be used whenever possible because of convenience, flexibility, and steady serum levels.



D. Transdermal fentanyl provides analgesia for up to 72 hours. The analgesic effects of methadone do not correlate with its long half-life.



C. Morphine is metabolized by hepatic glucuronidation.



B. Oxycodone is metabolized through CYP450 2D6 to active metabolites. Fast metabolizers—those with multiple copies of the CYP450 2D6 gene—would clear oxycodone and its metabolites quickly.



B. About 90% of methadone is bound to plasma protein and is widely distributed in tissues. Methadone has a long terminal half-life, resulting in slow clearance. This half-life does not correspond to analgesic dosing. It is metabolized via the CYP450 enzyme system.



A. Naloxone is a μ antagonist useful in opioid overdose. Naltrexone is also a μ antagonist, but it is reserved for use in alcoholism and opioid addiction.



D. Hydromorphone is an opioid with a short half-life with no available long-acting formulation. Thus, it is not useful as an around-the-clock medication.



C. Normeperidine, a metabolite of meperidine, can accumulate with chronic use, with renal impairment, and when the dose exceeds 600 mg every 24 hours.



E. The anticholinergic effects of tricyclic antidepressants such as Elavil can exacerbate opioid-induced constipation and urinary retention.



D. Because transdermal delivery bypasses absorption from the GI tract, constipation has been reported to be less frequent than with other opioids.



C. Caffeine has analgesic and possibly anti-inflammatory properties. Therefore, reduced doses of acetaminophen and aspirin may be required. Caffeine may also increase gastric acidity and perfusion, enhancing the absorption of aspirin.



A. Sumatriptan is a selective serotonin agonist.



E. Adverse effects of ergotamine include nausea and vomiting, physical dependence, muscle weakness, and angina-like pain. Overuse of ergotamine can result in ischemia that may progress to gangrene.



B. Triptans are contraindicated in pregnancy and ischemic cardiovascular disease. They cannot be used within 24 hours of another triptan or ergot alkaloid.



B. Good evidence exists for the efficacy of butorphanol nasal spray in migraine abortive therapy. Although opioids are commonly used for abortive therapy, they may be associated with rebound headaches and physical dependence.



A. With long-term therapy, methysergide can cause retroperitoneal, pleuropulmonary, and cardiac fibrosis. Fibrotic changes, although rare, are serious.



D. Midrin may be useful for mild to moderate migraines. It is generally well tolerated but may cause sedation. Because of Midrin's acetaminophen content, use of other acetaminophen products should be limited.



D. In contrast to ergotamine, DHE causes minimal peripheral vasoconstriction, little nausea and vomiting, and no physical dependence. However, diarrhea is prominent.



C. Prophylactic therapy should be considered because his migraines occur more than twice monthly and there is a trend toward increasing frequency of attacks.



B. Propranolol has been shown to be effective for migraine prophylaxis. This agent can reduce the number and intensity of attacks in about 70% of patients. Butorphanol, acetaminophen, dihydroergotamine, and hydrocodone are not approved for migraine prophylaxis.


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Hutchison TA, Shahan DR, eds. DRUGDEX® System. MICROMEDEX, Greenwood Village, Colo. (vol. expired March 2003).

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Opana [package insert]. Chadds Ford, Pa.: Endo Pharmaceuticals; 2008.

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Portenoy RK. Opioid therapy for chronic nonmalignant pain: A review of the critical issues. J Pain Symptom Manage. 1996;11:203-17.

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