Pharmacotherapeutics for Advanced Practice A Practical Approach THIRD EDITION (3)

Second-Line Therapy If the patient continues to have insomnia with first-line treatments, alternatives include switching to a benzodiazepine agent or using the other benzodiazepine receptor agonist, zolpidem. Again, t ...

Second-Line Therapy If the patient continues to have insomnia with first-line treatments, alternatives include switching to a benzodiazepine agent or using the other benzodiazepine receptor agonist, zolpidem. Again, the prescriber must consider the kind of sleep defect being treated and select a drug with the appropriate onset and half-life. Third-Line Therapy The practitioner should reassess the insomnia situation for patients who fail to respond to both first- and second-line therapies. Insomnia that has become chronic benefits most from continual evaluation and behavioral therapy along with the smallest dose possible of hypnotic medication. An antidepressant may play a key role at this level. Special Population Considerations Pediatric Use of barbiturates in the pediatric population is usually limited to those who have seizure disorders. In general, Arcangelo_Chap42.indd 661 10/8/2011 2:19:59 PM 662 UNIT 9 | PHARMACOLOGY FOR NEUROLOGICAL/PSYCHOLOGICAL DISORDERS benzodiazepines are not indicated for children younger than age 15. Caution is necessary when very young patients use antihistamines because of potential delirium or paradoxical excitation. Melatonin may be considered as treatment for a limited time (Ivanenko, et al., 2003). Geriatric It is important to evaluate the geriatric patient for underlying comorbidities that contribute to insomnia. Treating the underlying illnesses is important and may assist with re-establishing good sleeping patterns. Extreme caution is essential when prescribing hypnotic medications to elderly patients because these drugs can increase the potential for delirium and subsequent falls. In 1996, Zisselman, et al., analyzed hospital costs for the elderly when sedative-hypnotics were used to promote sleep. They found a statistically significant increase in cost resulting from increased length of hospital stay for patients who took sedative-hypnotics. In 1990, Shorr, et al., analyzed the quantity of prescriptions given to elderly patients along with the number of refills. Their concern was the overuse of the agents and the risks at which they place elderly patients over time. They found that many different physician groups were overprescribing sedative-hypnotics. Consistent monitoring of the elderly patient can be extremely important, especially when a long-acting hypnotic is prescribed. Antihistamines can cause delirium or paradoxical excitation. Women No sex differences exist in terms of the pharmacokinetics of the various agents used to treat sleep disorders. Caution is essential when prescribing all drugs to lactating women and women of childbearing age. Both antihistamines and zaleplon are pregnancy category C, whereas the barbiturates and benzodiazepines are pregnancy category D. Zolpidem, in category B, is in the lowest-risk pregnancy category. MONITORING PATIENT RESPONSE Sleep can be a reliable predictor of psychological and physical health. Differences in monitoring are related to whether the insomnia is an acute or chronic problem. Brief episodes of acute insomnia can warrant treatment, with the goal of preventing it from progressing and becoming chronic. A short course (up to 4 weeks) of sedative-hypnotic therapy is the current treatment of choice. Cognitive therapy can be included to improve the chance of an optimal response. When insomnia becomes a chronic problem, consistent interaction between the patient and health care provider is important, as is the use of behavioral techniques. With chronic insomnia, issues of drug tolerance for the older benzodiazepines and rebound insomnia usually become paramount. Current U.S. Food and Drug Administration guidelines allow only short-term prescription of hypnotic agents. National Center on Sleep Disorders Research (NCSDR) http://www.nhlbi.nih.gov/about/ncsdr National Heart, Lung, and Blood Institute (NHLBI) Health Information Network http://www.nhlbi.nih.gov Restless Legs Syndrome Foundation http://www.rls.org Sleep Foundation http://sleepfoundation.org BOX 42.4 Sleep Websites Tolerance and rebound insomnia have been cited as problems associated with these agents, but few studies have borne this out. In practice, many people take low-dose hypnotic agents for long periods with few side effects. Caution is warranted, however, if a patient requires escalation of a previously stable dosage. Careful analysis of changes in the patient’s sleep patterns is necessary in this event. Patient Education Patient education plays a key role in the treatment of insomnia. A key side effect of most hypnotic agents is excessive drowsiness or hangover from the medication. The clinician must alert the patient to this possibility and monitor the side effects of each agent prescribed. (See Table 42.1 and Table 42.2.) Patient-Oriented Information Sources Major sleep centers across the country have websites that are useful resources for patients and health care providers. These sites can provide information about diagnosis of sleep disorders and current research and therapies (Box 42.4). Nutrition/Lifestyle Changes Good sleep habits include setting a routine bedtime, getting regular exercise, using the bed for sleeping only, and getting in bed only when ready for sleep. Stimulants such as caffeine, alcohol, and excess fluids should be avoided before bedtime. Complementary and Alternative Medications Herbs and botanicals are often used as a “natural” way of promoting sleep. However, this is not without a certain danger, especially if these treatments are taken in conjunction with prescription drugs. Older patients are often likely to use herbal treatments: in 1997, it was reported that up to 3 million individuals over age 65 use such therapy (Desai & Grossberg, 2003). Melatonin, an endogenous hormone, is synthesized by the pineal gland from tryptophan. It is mainly secreted at night and its level peaks during normal sleep hours. In Arcangelo_Chap42.indd 662 10/8/2011 2:19:59 PM CHAPTER 42 | INSOMNIA AND SLEEP DISORDERS 663 1997, Lavie discovered that endogenous melatonin opens the nocturnal sleep gate and increases nocturnal melatonin secretion. Melatonin does not induce sleep but acts as a gatekeeper in the cascade of events that enables the CNS to favor sleep over wakefulness. Most studies have examined the use of melatonin to treat sleep disorders resulting from jet lag; few have looked at the use of melatonin in primary insomnia. A 1996 study by Attenburrow and Dowling on melatonin and primary insomnia examined healthy volunteers compared with the elderly. Through analysis of urine concentrations of endogenous melatonin, the study found that the elderly volunteers had a lower concentration of the melatonin metabolite and a delayed onset to peak secretion. These findings supported the possibility that some patients, especially those with delayed sleep phase insomnia, may benefit from the administration of exogenous melatonin; however, further study is necessary. Valerian is a traditional sleep remedy that is derived from the perennial herb Valeriana officinalis. The direct physiologic activity is mediated by the active sesquiterpene components of the volatile oil. This creates a synergistic effect with neurotransmitters such as GABA and produces a direct sedative effect. Effective dosage ranges from 300 to 600 mg of the valerian root; 2 to 3 g of the dried root is soaked in a cup of hot water for 10 to 15 minutes, and the patient then drinks the tea. Administration can occur 30 minutes to 2 hours before bedtime. Significant herb or drug interactions have not been reported by the German E Commission. RESTLESS LEG SYNDROME AND PERIODIC LIMB MOVEMENT DISORDER Restless leg syndrome (RLS) and periodic limb movement disorder (PLMD) are neurologic disorders. RLS is characterized by an intense need to move the legs, accompanied by paresthesias and dysesthesias that worsen usually in the evening. Sometimes the sensations can occur in other large muscle groups, but most often the legs are involved. Moving around relieves the feeling, but only for a short time, as the sensation soon returns. These sensations interfere with sleep. PLMD is characterized by episodes of highly repetitive and stereotyped limb movements only during sleep. Both disorders interfere with sleep and contribute to sleep deprivation and decreased alertness and daytime function. Indications are that 2% to 15% of the population may experience RLS, but the diagnosis is made rarely in primary care. CAUSES As a primary CNS disorder, RLS can be found in patients with end-stage renal disease, anemia, and sometimes in pregnancy (Gigli et al., 2004). RLS can also be hereditary or drug induced. 1. A compelling urge to move limbs associated with paresthesias/dysesthesias 2. Motor restlessness as evidenced by: • Floor pacing • Tossing and turning in bed • Rubbing legs 3. Symptoms worse or exclusively present at rest with variable and temporary relief by activity 4. Symptoms worse in the evening and at night BOX 42.5 Diagnostic Criteria for Restless Leg Syndrome Allen (2004) argued that iron deficits may be a strong cause of RLS, altering the iron–dopamine linkage, but this hypothesis needs further study. PATHOPHYSIOLOGY RLS and PLMD are sensory-motor disorders that are not well understood. Primary RLS has a strong hereditary component, with 40% to 60% of patients having a familial association. Onset of familial RLS is before the age of 30 years, and studies have indicated the strong action of a single major gene (Zucconi & Ferini-Strambi, 2004). Secondary RLS can be associated with neuropathies from changes in axonal and small-fiber neural pathways. Patients with rheumatoid arthritis and diabetes also have shown a greater prevalence of RLS, again presumably from changes due to neuropathy. Parkinson’s disease is frequently associated with RLS, pointing to a commonality in reduced dopaminergic functioning (Zucconi & Ferini-Strambi, 2004). A strong link has been established to the dopaminergic system by the positive response to the dopaminergic agonist classification of drugs (Allen, 2004). DIAGNOSTIC CRITERIA RLS is diagnosed primarily through the patient history. Clinical criteria have been established by the International Restless Legs Syndrome Study Group (Box 42.5). PLMD is associated more with stereotyped repetitive movements of limbs (legs alone, or legs more than arms) that occur only during sleep. PLMD is generally diagnosed only through a sleep test. The physical examination for RLS and PLMD should include a full neurologic examination with emphasis on the spinal cord and peripheral nerve function. A vascular examination is also necessary to rule out vascular disorders. Secondary causes of RLS should be evaluated by a serum ferritin level and serum Arcangelo_Chap42.indd 663 10/8/2011 2:19:59 PM 664 UNIT 9 | PHARMACOLOGY FOR NEUROLOGICAL/PSYCHOLOGICAL DISORDERS chemistry to rule out uremia and diabetes. Polysomnography is not routinely indicated for RLS but can be helpful to establish the diagnosis. Box 42.6 lists other possible diagnoses. INITIATING DRUG THERAPY Pharmacotherapy should be tailored for each patient. Patients with relatively mild symptoms may not need medications. Nonpharmacologic therapy should be instituted, including mental alerting activities and cessation of alcohol, nicotine, and caffeine. Any medications that may precipitate or worsen RLS symptoms, such as antidepressants and dopamine antagonists, should be avoided. Correction of underlying serum iron deficits may be helpful. Short-term studies have shown that drug therapy has significant benefits, but little is known about longterm treatment. A 3-year study of 70 patients by Clavadetscher et al. (2004) found that a good long-term response with drug therapy can be achieved in 80% of patients. This study helped to establish the benefit of pharmacologic therapy in RLS. Goals of Drug Therapy The goal of drug therapy is to calm the restless legs or periodic limb movements. Some patients can be refractory to pharmacologic treatment but still achieve partial relief of their symptoms. Pharmacologic agents for RLS include dopaminergic agents, dopamine agonists, opioids, benzodiazepines, anticonvulsants, and iron. (See Table 42.1.) Other than dopamine agonists, many of these drugs are being used in an “off-label” manner. Dopaminergic Agents These drugs are dopamine precursor combinations such as carbidopa–levodopa (Sinemet). These agents are useful for intermittent RLS because they have a quicker onset than dopamine agonists. This is useful for relief of sleep onset insomnia and 1. Nocturnal leg cramps • Painful, palpable involuntary muscle contractions • Focal with sudden onset • Unilateral 2. Akathisia Excessive movement without accompanying sensory complaints 3. Peripheral neuropathy • Usually tingling, numbness, or pain sensations • Not associated with motor restlessness • Not helped by movement • Evening or nighttime worsening BOX 42.6 Differential Diagnoses for RLS and PLMD RLS that occurs during long car or airplane journeys. Dosage of these agents is lower than used for Parkinson’s disease. Adverse Events The carbidopa–levodopa agents may actually worsen RLS symptoms in up to 80% of patients. The therapeutic effect may be reduced if taken with high-protein food. Insomnia, sleepiness, and gastrointestinal problems are other adverse events. Dopamine Agonists The initial dopamine agonists used for RLS were bromocriptine and pergolide, which were prone to side effects. The newer dopamine agonists, such as pramipexole and ropinirole, are not ergot based; while they have fewer side effects, they can cause initial nausea and lightheadedness, nasal stuffiness, edema, and rarely daytime sleepiness. Increasing the dose slowly will help to mitigate these side effects. Opioids Opioids are reserved for the most severe cases of RLS or PLMD that are refractory to treatment with other pharmacologic agents. This class of medications can be used on a daily or intermittent basis. Clinical experience by sleep experts suggests that only a few patients will require opioids (Silber, 2004). Benzodiazepines Benzodiazepines (see Table 42.1) are used concomitantly with a dopamine agonist when use of a sole agent has failed. Clinical experience is particularly crucial with clonazepam and temazepam. These drugs may be helpful for patients who cannot tolerate the other medications. Caution is necessary when using these agents with the elderly, and they can cause daytime sleepiness and cognitive impairment. Anticonvulsants Anticonvulsants are considered when dopamine agonists have failed and in patients who describe the RLS discomfort as pain. Gabapentin is helpful in patients with RLS and peripheral neuropathy. It is useful in treatment of daily RLS. As with the dopamine agonists, lower dosages of gabapentin (100 to 600 mg one to three times daily) can be successful. The side effect of hypersomnia often limits the dosage. Other side effects can include nausea, sedation, and dizziness. See Chapter 39 for further discussion. Selecting the Most Appropriate Agent For treatment purposes, RLS can be classified as intermittent (not often enough to require drug therapy), daily (troublesome enough to require drug therapy), and refractory (not adequately treated by a dopamine agonist). The ideal agent will minimize or abate the symptoms of RLS. No one pharmacologic agent appears to help all patients, and often a combination of medications is needed. The severity of RLS can vary, and pharmacologic treatment needs to be individualized. See Box 42.7 for considerations when selecting a pharmacologic agent (Figure 42-2). Arcangelo_Chap42.indd 664 10/8/2011 2:19:59 PM CHAPTER 42 | INSOMNIA AND SLEEP DISORDERS 665 Age of patient Benzodiazepines can cause cognitive impairment in elderly. Severity of symptoms Mild symptoms: no medication, or levodopa or dopamine a gonist Severe symptoms: strong opioid Frequency/regularity of symptoms Patients with infrequent symptoms may benefit from prn medication. Presence of pregnancy No safety and efficacy clinical trials on treatment of RLS with medications in pregnancy Renal failure Need to decrease dosage if drugs are renally excreted Considerations in Pharmacologic Agent Selection in RLS BOX 42.7 Identification of symptoms: "Creepy, crawly feeling" worse at night Must walk to relieve symptoms H & P Labs: CBC, ferritin level (treat low iron) Review medications Intermittent symptoms Persistent symptoms Persistent with neuropathy Refraction symptoms Change to a different dopamine agonist Add low-dose opioid Treat prn with carbidopa/ levodopa Trial dopamine agonist: ropinirole, pramixole Gabapentin Key Starting point for decision making Clinial actions (assessing, prescribing, monitoring) Decision point FIGURE 42–2 Algorithm for treatment for RLS. Arcangelo_Chap42.indd 665 10/8/2011 2:19:59 PM 666 UNIT 9 | PHARMACOLOGY FOR NEUROLOGICAL/PSYCHOLOGICAL DISORDERS First-Line Therapy Dopaminergic antagonists such as low-dose carbidopa– levodopa should be reserved for patients with intermittent RLS. The first choice of therapy for daily RLS is one of the dopamine agonists. The largest placebo-controlled trial has been conducted on ropinirole (Requip) (Trenkwalder, et al., 2004). Other medications in this class include pramipexole (Mirapex). Nausea, dizziness, dyskinesia, and somnolence are potential side effects of both the dopaminergic antagonists and agonists. Second-Line Therapy Pharmacologic agents approved for neuropathic pain such as gabapentin (Neurontin) can be used alone or in conjunction with other agents. It is especially helpful for patients who describe RLS symptoms as painful. Other anticonvulsant agents such as carbamazepine (Tegretol) can be considered, but the older agents carry an increased risk of side effects such as dizziness, drowsiness, and lack of coordination. Patients also may experience nausea with these older agents. An opioid or opioid receptor agonist, tramadol (Ultram), may be added or used alone at low doses. If either the anticonvulsant or opioid fails, a repeat trial of dopamine agonists should be attempted (Silber, 2004). Third-Line Therapy Patients who continue to have symptoms may be refractory to treatment. Therapeutic doses may not have been obtained, or the patients could not tolerate the side effects of the medications. Substitution of different medications in the dopamine agonist class or adding higher-potency opioids should be considered. Consultation with a sleep specialist should be considered. Monitoring Patient Response Most patients will have remittance of symptoms with the first therapeutic dose of medication. This supports the theory that dopaminergic abnormality is a cause of this disorder. Another indicator of improvement is a decrease in excessive daytime sleepiness from lack of REM sleep. Patients need to be monitored for side effects of the pharmacologic agents. The longterm efficacy of these pharmacologic agents is uncertain, and monitoring for relapse of symptoms is important. It is also important to monitor for dependence when benzodiazepines or opioids are used. PATIENT EDUCATION Many patients who have RLS use OTC sleep medications, and poor sleep hygiene may contribute to the lack of sleep in RLS sufferers. Implementing cognitive sleep hygiene techniques may provide a modest improvement in short-term sleep symptoms (Edinger, 2003). Patients should inform all of their health care providers about their RLS diagnosis, and health care providers should be aware that the patient’s inability to keep his or her limbs still is not due to lack of cooperation. Improper restraint of patients with this syndrome has resulted in mortality and morbidity. Drug Information A higher dosage of ropinirole (Requip) is needed compared to pramipexole (Mirapex) to achieve the same therapeutic effect. This may contribute to side effects and tolerability of the drug. Patient-Oriented Information Sources The Restless Legs’ Syndrome Foundation supports research and provides information for patients and health care providers. Extensive international research is also being conducted on this serious sleep problem. (See Box 42.4.) NARCOLEPSY Narcolepsy is a sleep disorder caused by malfunctions in the primary brain mechanism that induces sleep. Individuals with narcolepsy achieve REM sleep in less than a minute, bypassing the other sleep stages. The other features of narcolepsy include excessive daytime sleepiness, cataplexy (attacks of muscle weakness), sleep paralysis, and hypnagogic hallucinations. Narcolepsy is the second leading cause of excessive daytime sleepiness and has an overall incidence in the world of 0.2 to 1.6 per thousand individuals (Stanford Center for Narcolepsy, 2004). Narcolepsy can have a dramatic impact on virtually all areas of life. CAUSES Narcolepsy usually starts in the second or third decade of life, but it has been identified in children as young as age 3. Excessive daytime sleepiness or cataplexy may be the first symptoms, but most often cataplexy is delayed 2 to 3 years. Cataplexy attacks are often precipitated by highly specific situations or triggers of strong emotions. Hypnagogic hallucinations can be present but are rarely the first manifestation of narcolepsy. PATHOPHYSIOLOGY The pathophysiology of narcolepsy is not well understood. It appears to be a disease where daily periods of internal clock-dependent alerting appear to be missing. Narcolepsy is sporadic and without a familial predisposition. Some evidence has shown a genetic component with specific human leukocyte antigens. It is possible that hypocretin-producing Arcangelo_Chap42.indd 666 10/8/2011 2:20:00 PM CHAPTER 42 | INSOMNIA AND SLEEP DISORDERS 667 cells express toxins that provoke an autoimmune cascade that triggers narcolepsy. DIAGNOSTIC CRITERIA The International Classification of Sleep Disorders states that individuals with narcolepsy have excessive sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations (the “narcoleptic tetrad”). Many narcolepsy patients also have disrupted nighttime sleep and automatic behaviors. Not all patients with narcolepsy have all symptoms of the narcoleptic tetrad, but excessive sleepiness is present in virtually every patient. Silber et al. (2002) researched whether including human leukocyte antigen (HLA) typing provides a higher reliability of diagnosis. They used clinical and neurophysiologic data to evaluate 69 patients in four categories: definite narcolepsy, probable narcolepsy with two subgroups (confirmed by laboratory study), and probable narcolepsy (clinical). Seventy-four percent of patients had a positive HLA that helped to confirm the diagnosis of narcolepsy. INITIATING DRUG THERAPY There is no cure for narcolepsy, and pharmacologic therapy must be initiated to control the attacks. Evaluation for cataplexy, hypnagogic hallucinations, and sleep paralysis is important to identify the best agent for treatment. Most often antidepressants are used to block the REM paralysis of cataplexy. The mainstay of pharmacologic therapy until now has been amphetamines and amphetamine-like drugs such as methylphenidate (Ritalin). These are used to combat the abnormal sleepiness. Two newer pharmacologic agents that accomplish the same effect as amphetamines are modafinil (Provigil) and armodafinil (Nuvigil). These agents are nonamphetamines and are classified as Schedule IV controlled substances. Goals of Drug Therapy Pharmacologic therapy should be titrated to promote the optimal dose of stimulation. The health care provider needs to work with the patient to identify personal treatment goals such as staying awake in a classroom or social situation or while driving. The main goal is to achieve as normal a life as possible, staying awake in situations of normal daily living. Psychostimulants Modafinil and armodafinil (the R-enantiomer of modafinil) are psychostimulants with unique properties to promote wakefulness. The potential for abuse of these agents is much lower than with other stimulants, although it still needs to be monitored. The mechanism of action of modafinil and armodafinil is not well understood, but it appears to attenuate the central alpha-1 adrenergic system. The primary sites of action are the subregions of the hippocampus, the centrolateral nucleus of the thalamus, and the central nucleus of the amygdala. Modafinil can produce euphoria and psychoactive effects similar to other CNS stimulants. Absorption of the drug occurs rapidly, with peak plasma concentration in 2 to 4 hours and a half-life of 15 hours. Distribution of the drug is throughout the tissues, and it is moderately bound to plasma proteins. The drug is metabolized in the liver and excreted in the urine. In a recent study of the long-term efficacy of modafinil conducted by the Narcolepsy Multicenter Study Group (Mitler, et al., 2000), the most common adverse side effects of the drug were headache, nausea, nervousness, and anxiety. Most side effects are mild to moderate and transient. (See Table 42.1.) SPECIAL POPULATIONS Pediatrics Modafinil has not been studied in children. The alternative drug of choice would be methylphenidate. Geriatrics Care must be taken when prescribing modafinil to the elderly population. The oral clearance of modafinil is reduced in the elderly by 20% to 50%. Renal failure does not influence the pharmacokinetics of the drug but does increase the inactive metabolite accumulation. Liver impairment can reduce the modafinil clearance and double serum concentrations. MONITORING PATIENT RESPONSE Narcolepsy is a life-long disease process, and patients must use the medications for their entire lives. Patient response is monitored by improvement in the disease’s severity. Achieving the goals identified by the patient can help to improve compliance. PATIENT EDUCATION Patients and their families need to be aware of all available options to treat narcolepsy. Psychological distress is a consequence, not the cause, of the disease. Discussion of potential side effects of the drugs is important for compliance. Offering counseling and support groups when necessary is important. Arcangelo_Chap42.indd 667 10/8/2011 2:20:00 PM 668 UNIT 9 | PHARMACOLOGY FOR NEUROLOGICAL/PSYCHOLOGICAL DISORDERS Case Study 1 . H., age 47, reports difficulty falling asleep and staying asleep. These problems have been ongoing for many years, but she has never mentioned them to her health care provider. She has generally “lived with it” and self-treated the problem with OTC Tylenol PM. Currently she is also experiencing perimenopausal symptoms of night sweats and mood swings. Current medical problems include hypertension controlled with medications. Past medical history includes childhood illnesses of measles, chickenpox, and mumps. Family history is positive for diabetes on the maternal side and hypertension on the paternal side. Her only medication is an angiotensin-converting enzyme inhibitor and diuretic combination for hypertension control. She generally does not like taking medication and does not take any other OTC products. DIAGNOSIS: INSOMNIA 1. List specific goals of therapy for S. H. 2. What drug therapy would you prescribe? Why? 3. What are the parameters for monitoring the success of the therapy? 4. Discuss specific patient education based on the prescribed therapy. 5. List one or two adverse reactions for the selected agent that would cause you to change therapy. 6. What would be the choice for second-line therapy? 7. What OTC and/or alternative medicines might be appropriate for this patient? 8. What dietary and lifestyle changes might you recommend? 9. Describe one or two drug–drug or drug–food interactions for the selected agent. S Case Study 2 . F., age 73, reports a “funny sensation in my legs at night.” To get rid of this sensation, she has to move. She can sleep only 2 or 3 hours at a time before the sensation wakes her up. This problem has been ongoing from her early twenties but has steadily worsened with age. She finds herself walking around a lot in the early evening. She has tried to self-treat the problem with OTC Tylenol PM. Current medical problems include hypertension, hyperlipidemia, coronary artery disease, and depression. Family history is positive for coronary artery disease on the paternal side. Medications include Prinivil 10 mg qd, Zocor 40 mg qd, Lexapro 10 mg qd, and ASA 81 mg qd. She does not want to take any more medication but wants to help her legs stop moving at night. DIAGNOSIS: RESTLESS LEG SYNDROME 1. List specific goals of therapy for J. F. 2. What drug therapy would you prescribe? Why? 3. What are the parameters for monitoring the success of the therapy? 4. Discuss specific patient education based on the prescribed therapy. 5. List one or two adverse reactions for the selected agent that would cause you to change therapy. 6. What would be the choice for second-line therapy? 7. What OTC and/or alternative medicines might be appropriate for this patient? 8. What dietary and lifestyle changes might you recommend? 9. 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He also reports excessive daytime sleepiness, which he cannot understand since he is usually in bed by 10 pm and doesn’t get up until 8 am. This has been a problem for about the past 6 months. His family history is negative for any illnesses and sleep disorders. He does not take any medications or OTC products routinely. DIAGNOSIS: POSSIBLE NARCOLEPSY 1. List specific goals of therapy for D. W. 2. What drug therapy would you prescribe? Why? 3. What are the parameters for monitoring the success of the therapy? 4. Discuss specific patient education based on the prescribed therapy. 5. List one or two adverse reactions for the selected agent that would cause you to change therapy. 6. What would be the choice for second-line therapy? 7. What OTC and/or alternative medicines might be appropriate for this patient? 8. What dietary and lifestyle changes might you recommend? 9. Describe one or two drug–drug or drug–food interactions for the selected agent. 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(2004). Geriatric Psychopharmacology Update, 8(1), 1–6. *Zisselman, M., Rovner, B., Yuen, E., & Louis, D. (1996). Sedative-hypnotic use and increased hospital stay and costs in older people. Journal of the American Geriatric Society, 44, 1371–1374. *Zucconi, M., & Ferini-Strambi, L. (2004). Epidemiology and clinical findings of restless legs syndrome. Sleep Medicine, 5, 293–299. Arcangelo_Chap42.indd 670 10/8/2011 2:20:00 PM 671 CHAPTER Andrew M. Peterson 43 Dharmi Patel have been studied. These include a baseline norepinephrine level that is too high, a central epinephrine level that is too high, a problem with the functioning of epinephrine in the peripheral system, or problems involving dopamine receptors or dopamine-mediated functions (Pliszka, et al., 1996). All these mechanisms may work together to cause ADHD symptoms. The complete pathophysiologic process of these mechanisms is not completely understood, but there appears to be a connection between the D4 receptor and activity of the major neurotransmitters, epinephrine, norepinephrine and dopamine (Adler & Chua, 2002; Daley, 2004). Risk factors may be involved in the development of ADHD, although many are only associations and do not indicate that ADHD is present. The practitioner must ascertain the patient’s drug history and examine for visual disturbances and hearing dysfunction as possible causes of the child’s behavior (Dulcan, et al., 1997). A rare genetic disorder, generalized resistance to thyroid hormone, has been associated with ADHD (Hauser, et al., 1993). Fragile X syndrome, fetal alcohol syndrome, glucose-6-phosphate dehydrogenase deficiency, and phenylketonuria are also associated risks for development of ADHD (Dulcan, et al., 1997). Limited numbers of cases have been associated with other risk factors, including such pregnancy variables as poor maternal health, young maternal age, maternal use of alcohol or cigarettes, toxemia or eclampsia, postmaturity, and extended labor (Dulcan, et al., 1997; Markussen, et al., 2003). Medical conditions and malnutrition in infancy may also play a role in ADHD, although this has not been proved (Dulcan, et al., 1997). DIAGNOSTIC CRITERIA The diagnostic criteria for ADHD are listed in Box 43.1. Children are required to show symptoms by age 7, and most children show symptoms for many years before the diagnosis is made (APA, 2000). For a definitive diagnosis, the child also must show symptoms in more than one setting, such as at home and in school. The adult with ADHD may display symptoms at home and at work. Adult patients also have trouble maintaining relationships as a result of their inattentiveness. In children and adults, the symptoms must interfere with Attention-Deficit/Hyperactivity Disorder Attention-deficit/hyperactivity disorder (ADHD) has become a commonly diagnosed condition among today’s children. Hallmark symptoms include hyperactivity, impulsivity, and inattention. The American Psychiatric Association (APA) estimated in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) that 3% to 5% of school-aged children had ADHD. The disorder is more common in boys than in girls, with a ratio ranging from 4:1 to 9:1 (APA, 2000; Spencer, et al., 2002). Research is increasingly revealing that ADHD also affects adults, with estimates of prevalence ranging from 2% to 7% (Wender, 1995). This realization is changing perceptions of ADHD because it is becoming imperative to understand the disorder as diagnosed in adulthood. Researchers have found that many of the core symptoms of ADHD are treatable. Treatment should be individualized to the patient’s symptoms. The treatment plan usually is multimodal. Even when treatment begins early in childhood, the patient may still show symptoms in adolescence or adulthood. The outcome of the childhood disorder is uncertain, as is determining which children will have the disorder. CAUSES Many causes of ADHD have been suggested, but none has yet to be accepted. Evidence suggests that the disorder may have a genetic link (Farone & Biederman, 1994). Estimates are that children who have a sibling with ADHD have a two to three times greater chance of being diagnosed with ADHD (Dulcan, et al., 1997). Growing evidence suggests that the principal cause of ADHD is genetic (Pliszka, 2007). ADHD has been associated with the dopamine transporter gene and the dopamine D4 gene (Adler & Chua, 2002; Daley, 2004). Possible nongenetic causes are neurobiological, such as perinatal stress, low birth weight, traumatic brain injury, maternal smoking during pregnancy, and severe early deprivation (Pliszka, 2007). Other theories involve dietary intake of certain chemicals and sugars, but data are lacking. PATHOPHYSIOLOGY Neurotransmitter dysfunction is a proposed mechanism for ADHD, and several different pathways for this dysfunction Arcangelo_Chap43.indd 671 10/8/2011 2:20:15 PM 672 UNIT 9 | PHARMACOLOGY FOR NEUROLOGICAL/PSYCHOLOGICAL DISORDERS the person’s ability to function. The criteria are further broken into subtypes, and based on the symptoms, the patient’s disorder is coded (Box 43.2). Diagnosing ADHD in a child may be difficult because children often behave differently in the health care setting, therefore making it impossible for the provider to observe symptoms. For this reason, the practitioner must use other methods to evaluate behavior. Such methods include rating scales, which usually are administered by parents and teachers. All scales are similar, but each has its own criteria and rating system. Some commonly used scales include the parent-completed Child Behavior Checklist (Achenbach, 1991; Biederman, et al., 1993), the Teacher Report Form of the Child Behavior Checklist (Achenbach, 1991; Edelbrock, et al., 1984), the Conners Parent and Teacher Rating Scale (Ullmann, et al., 1985), the Barkley Home Situations Questionnaire and School Situations Questionnaire (Barkley, 1990), and the Child Attention Problems Profile (Barkley, 1990; Barkley et al., 1989). These rating scales have been found to be accurate measures of ADHD behavior (Dulcan, et al., 1997). Practitioners may use these rating scales to follow a child’s behavior after the initial diagnosis of ADHD. Making the initial diagnosis also requires detailed parent interviews that focus on a family history of ADHD or other psychiatric disorders, psychosocial adversity (e.g., poverty, parental psychopathology or absence, family conflict), school behavior, learning, attendance and test reports, and medical evaluations (Dulcan, et al., 1997). A. Either (1) or (2) 1. Six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Inattention a. often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities b. often has difficulty sustaining attention in tasks or play activities c. often does not seem to listen when spoken to directly d. often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions) e. often has difficulty organizing tasks and activities f. often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework) g. often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools) h. is often easily distracted by extraneous stimuli i. is often forgetful in daily activities 2. Six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Hyperactivity a. often fidgets with hands or feet or squirms in seat b. often leaves seat in classroom or in other situations in which remaining seated is expected c. often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness) d. often has difficulty playing or engaging in leisure activities quietly e. is often “on the go” or often acts as if “driven by a motor” f. often talks excessively Impulsivity g. often blurts out answers before questions have been completed h. often has difficulty awaiting turn i. often interrupts or intrudes on others (e.g., butts into conversation or games) B. Some hyperactive–impulsive or inattentive symptoms that caused impairment were present before age of 7 years. C. Some impairment from the symptoms is present in two or more settings (e.g., at school [or work] and at home). D. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning. E. The symptoms do not occur exclusively during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for by another mental disorder (e.g., Mood Disorder, Anxiety Disorder, Dissociative Disorder, or Personality Disorder). Criteria for Diagnosing Attention-Deficit/Hyperactivity Disorder BOX 43.1 From American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text revision) . Washington, DC: Author, with permission. Arcangelo_Chap43.indd 672 10/8/2011 2:20:16 PM CHAPTER 43 | ATTENTION-DEFICIT/HYPERACTIVITY DISORDER 673 A confounding factor in the diagnosis is the probability of comorbid disorders. Mood disorders, anxiety disorders, learning disorders, and communication disorders are more common in the child with ADHD (APA, 2000). Laboratory findings, physical examination, and evaluation of concurrent medical problems cannot be used to confirm the diagnosis. Minor physical anomalies such as hypertelorism, a highly arched palate, and low-set ears may be more common in this population (APA, 2000), but such characteristics do not mean that the child has ADHD. Many children diagnosed with ADHD can be expected to have some impaired social functioning in adult life. The diagnosis of ADHD in the adolescent is less clear since as an ADHD child matures into adolescence, the symptoms change (Nahlik, 2004). Moodiness, laziness, boredom, or impatience may be common symptoms in the ADHD adolescent but may also be typical adolescent behavior or even another mood disorder. Diagnosis in an adult consists of a complete psychiatric evaluation; childhood history; information from spouse or significant others, parents, or employers; and a review of school records. A medical history and physical examination can be used to rule out comorbid conditions. As with childhood diagnosis, rating scales and questionnaires may also be used (Weiss & Murray, 2003), such as the Conners Abbreviated Teacher’s Rating Scale and the Wender Utah Rating Scale. Practitioners cannot use a patient’s response to stimulant therapy to determine ADHD status. A child not diagnosed with ADHD has the same response of reduced hyperactivity, impulsivity, and inattentiveness as a child diagnosed with ADHD (Goldman, et al., 1998). INITIATING DRUG THERAPY Many practitioners today follow a multimodal treatment plan. Multimodal treatment plans seem logical because different symptoms respond to different types of treatment. The Multimodal Treatment Study (MTA) showed that children receiving intensive behavioral management combined with medication fared better than those receiving intensive behavioral management alone (Anonymous, 1999). The core symptoms of the disorder (i.e., inattention, hyperactivity, and impulsivity) respond to medication, with or without the behavioral intervention. Behavioral symptoms seem to respond to environmental modification, while skills in sports, academics, and social situations may not respond to medication or behavior modification. Relationship problems usually can be treated through psychotherapy. Nonpharmacologic aspects of a multimodal treatment plan consist of behavior modification, parent training, family therapy, social skills training, academic skills training, individual psychotherapy, cognitive behavior modification, and therapeutic recreation. These are discussed further in the Nutrition/ Lifestyle section later in this chapter. Goals of Drug Therapy When a child is diagnosed with ADHD, questions arise regarding the outcome of this disorder. Parents want to know if there is a cure and, if so, what treatment will increase the chance for cure. However, the outcome of ADHD cannot be predicted, and the child will not always “grow out of it.” Three outcomes have been identified. The first possible outcome is developmental delay, which occurs in approximately 30% of diagnosed children; this means that the child will outgrow the symptoms. The second possible outcome, which occurs in 40% of children, is continual display, which is marked by adult life with ADHD. Continual display may lead to social and emotional difficulties. The third possible outcome is developmental decay (30% of children with ADHD), which involves the continual display of core ADHD symptoms along with pathologic conditions such as substance abuse and antisocial personality disorder. Developmental decay is the most severe outcome (Sudak, 1998). Medication therapy is usually one of the first options in treating patients newly diagnosed with ADHD. Pharmacotherapy offers several alternatives (Table 43.1). The medication class primarily used is stimulants, such as amphetamines and methylphenidate. Nonstimulant alternatives are atomoxetine (Strattera), buproprion (Wellbutrin), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase (MAO) inhibitors and alpha-adrenergic agonists (Pliszka, 2007). Although it is not clear how these medications actually affect the primary symptoms of ADHD, it is known which neurotransmitters they affect (Table 43.2). 314 .01 Attention-Deficit/Hyperactivity Disorder, Combined Type: if both Criteria A1 and A2 are met for the past 6 months 314 .00 Attention-Deficit/Hyperactivity Disorder, Predominantly Inattentive Type: if Criterion A1 is met but Criterion A2 is not met for the past 6 months 314 .01 Attention-Deficit/Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type: if Criterion A2 is met but Criterion A1 is not met for the past 6 months Coding note: For individuals (especially adolescents and adults) who currently have symptoms that no longer meet full criteria, “In Partial Remission” should be specified. From American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text revision, p. 93). Washington, DC: Author, with permission. BOX 43.2 Diagnostic and Statistical Manual of Mental Disorders—IV: Coding Based on Type Arcangelo_Chap43.indd 673 10/8/2011 2:20:16 PM 674 UNIT 9 | PHARMACOLOGY FOR NEUROLOGICAL/PSYCHOLOGICAL DISORDERS The long-term benefits of medication therapy have not been determined. It is clear that they work in the short term to improve symptoms, but there is a lack of long-term studies (Goldman, et al., 1998). The following information addresses concerns for the pediatric population using these medications. Stimulants A stimulant is usually the first-choice medication, based on 60 years of research and clinical experience (Dulcan, et al., 1997). Daley (2004) reported that nearly 70% of patients will respond to stimulant therapy. The most commonly used stimulants are methylphenidate (Ritalin, Concerta) and amphetamine salts (Adderall, Dexedrine). Either stimulant is appropriate; both are equally efficacious in the treatment of ADHD. Dosage Amphetamines should be started at the lowest dosage and titrated upward until the desired response is seen. Dosing is usually based on weight and titrated to a dosage that controls the symptoms of ADHD. Table 43.3 lists medications and their dosages. There is equal efficacy between long-acting and immediate-release formulations. Longer-acting formulations may provide improved convenience and compliance. A patient may be initially started on a long-acting form, but children (<16 kg) are often started on shorter-acting doses because long-acting forms are not manufactured in low doses (Pliszka, 2007). For immediate-release methylphenidate, the typical starting dose for children under age 6 is 5 mg before breakfast and 5 mg at lunch. The dose may be increased by 5 to 10 mg weekly, with a maximum recommended dose of 60 mg. Long-acting preparations are available if the immediate-release formulation is impossible or inconvenient to give, or if rebound is a problem. The long-acting methylphenidate Ritalin LA should be started after the patient is taking 20 mg of the immediate-release preparation. For patients taking 10 to 20 mg of immediate-release methylphenidate daily, Concerta 18 mg or Metadate ER 10 or 20 mg may also be used. Dose titrations occur every 1 to 3 weeks until the maximum allowed dose, symptom remission, or side effects prevent further titrations, whichever occurs first. Mechanism of Action As mentioned previously, it is not clear how stimulants help to reduce the core symptoms of ADHD. In addition to increasing levels of epinephrine and norepinephrine, these agents also can bind to central dopamine receptors and increase the systemic levels of dopamine. Adverse Events The primary adverse events related to stimulant therapy include palpitations, tachycardia, elevated blood pressure, and potentially arrhythmias. Changes in appetite, nausea, vomiting, and other gastrointestinal (GI) disturbances may occur. The neurologic adverse events range from headache and insomnia to seizure activity, particularly in patients predisposed to seizures. In general, adverse events are manageable, results are quick and predictable with the first dose, and the medications are easy to titrate (Buitelaar, et al., 1995). The adverse events of the stimulants, such as headaches, dizziness, appetite suppression, tics, dyskinesias, sleep disturbances, abuse potential, and in particular growth retardation (below height or weight on normal growth charts), may be of concern. One study found a significant difference in growth between patients who took stimulants and those who did not. Other studies have shown a decrease in height or weight in patients taking stimulants. The clinician must assess the growth progress, need for continued treatment, and overall functioning of the ADHD patient every 1 to 3 months (Daley, 2004).