Clonidine - Introduction

   "If attention and activity were a steam engine [Ritalin] increases the heat and applies the brakes; clonidine turns down the heat."

Hunt, 1988 (In: Copeland, 1991, p. 237)

   Experience with clonidine in clinical practice has shown it to be a very useful medication. Clonidine appears to be exquisitely sensitive in targeting and diminishing symptoms that arise from an overactive and/or over reactive autonomic nervous system.

Target Symptoms for Clonidine

A Brief History of Clonidine and Its Uses

Treating Hypertension

   Clonidine has been widely used in medicine since the 1970s for reducing excessive sympathetic tone and resultant autonomic physiologic effects such as elevated blood pressure. It has been approved by the Food and Drug Administration, and the safety of its use has been well documented in extensive literature dealing with adult hypertension.

   In recent years many new and thus more profitable antihypertensive medications have been developed, patented and marketed. The result has been that clonidine, now off patent and very inexpensive, has lost the enthusiasm of the manufacturers who prefer to promote new products still under patent. Clonidine, still very effective and useful, has tended to become over looked. Important roles remain, however, and new ones are appear continually for such alpha-2 agonists as clonidine.

   Oster and Epstein (1991) believed that these newer medications were, in some respects, inferior to clonidine. They considered this to be the case not only in the treatment of hypertension, but in a wide array of problems relating to autonomic hyperactivity. "Considerable evidence suggests that hyperactivity of the sympathetic nervous system is implicated not only in the pathogenesis of essential hypertension but also in several blood pressure-independent complications of essential hypertension. Even with the advent of newer antihypertensive agents, including angiotension-converting enzyme inhibitors and calcium antagonists, the centrally acting sympatholytics (alpha-2 adrenoceptor agonists) remain a valuable group of medications for the management of hypertension of all grades of severity"[p.1638-44].
      

The Rapid Emergence of New Off Label Uses: A Review of the Literature

   As clonidine waned in the treatment of hypertension, it was being rediscovered as a very useful aid in managing the symptoms of a wide range of neurobiological disorders. What these disorders appear to have in common was a hyper reactive central autonomic nervous system, particularly involving the noradrenergic system. What clonidine contributes to the treatment of all of these clinical syndromes is to reduce symptoms of excessive activation and arousal. Clonidine's effectiveness is a function of the degree to which the clinical symptoms are related to such noradrenergic dysregulation. (Hunt 1991).

   Clonidine, both alone and in combination with stimulants and other medications, has gained widespread acceptance in the clinical treating community.

   Johnston et al. (1995) estimated, for example, that more than 100,000 children in the United States were on a methylphenidate-clonidine combination. Clonidine's popularity has grown in spite of the fact that the type of formal clinical trials necessary to gain FDA approval for uses, other than in treating adult hypertension, have yet to be done. Following is a brief review of the medical and research literature currently available relating to the many emerging "off label" uses of clonidine.

Use in Treating Motor Tics

   Clonidine has been used to treat motor tics since 1979, especially when the tics are made worse by increased arousal (excitement, anxiety, etc). Motor tics are experienced as irresistible, often exacerbated by stress, suppressed for brief periods of time and during sleep, occur in bouts several times a day, and have their onset before age 21.

   Motor tics appear to reflect high noradrenaline and probably low serotonin as well. Tics often increase with any increase in arousal such as anxiety, or excitement. They can be inhibited voluntarily for short periods of time with conscious effort. A student who is focused on suppressing motor tics, however, is not paying attention to much else.

   Medications can have dramatic results in controlling tics. By either decreasing noradrenaline with clonidine, and/or increasing serotonin such as with a serotonergic antidepressant, tics usually are diminished. The older approach of using dopamine receptor blocking agents such as haloperidol (Haldol) also decrease motor tics as hyperactive motor pathways controlled by dopamine are involved.    Clonidine has been found to be an effective and much safer alternative to the more traditional dopamine blocking neuroleptics. Clonidine has distinctive advantages in that it is not known to pose a risk for causing tar dive dyskinesia. This is a serious and potentially irreversible movement disorder (Comings 1990) associated with most dopamine blocking agents. The blocking of dopamine receptors may also sacrifice attention and decrease learning and cognitive proficiency and are now avoided if possible. They are still used in controlling more severe symptoms when other treatments have failed and when the potential benefits outweigh their risks.

Use for Treatment of Tourette's Syndrome

   Tourette's syndrome (TS) is a neurobiological disorder characterized by changing motor and vocal tics, with associated symptoms of obsessive-compulsive ideas and behaviors and attention deficit disorder with hyperactivity.
Genetic factors seem to play a major role, but the precise mode of inheritance is still not known.
   Cohen and colleagues (1979, 1980) first reported that small doses of clonidine improve TS in children . Clonidine was observed to ameliorate the disorder in the majority of 25 patients who could not tolerate or did not benefit from treatment with haloperidol. Clonidine had a gradual onset of action. Compulsive behavior, frustration intolerance, speech difficulties, behavioral blocking, attentional problems, and tics were responsive to treatment. These results suggested that the noradrenergic system may be involved, primarily or secondarily, in the expression of the genetic predisposition to TS.
   Leckman and colleagues (1991) noted that TS patients experienced substantial, long-term symptomatic improvement with minimal side effects when taking clonidine. There was also significant improvement in motor and phonic tics. Associated behavioral symptoms appeared to show the most consistent improvement with maximum benefit achieved after 4 to 6 months of treatment. There were no serious side effects and tolerance to clonidine did not develop.
   As with simple motor tics until the 1980s, TS had most often been treated with the dopamine receptor blocker haloperidol. In studies by Borison and colleagues (1983) clonidine was shown to be equally efficacious with haloperidol, but did not produce adverse central nervous system side-effects.
   Singer and colleagues (1985) found that haloperidol improved tic symptoms in 50/60 patients, but side effects often nullified these benefits. Clonidine was helpful in 47% and caused few side effects.

Attention Deficit Hyperactivity Disorder (ADD/ADHD)

   Hunt (1985) extended this research to a group of children with ADHD. A controlled clinical trial demonstrated clonidine's usefulness in treating the symptoms of hyper arousal and hyper reactivity in certain children with ADHD. Hunt demonstrated that clonidine improved frustration tolerance, decreased motor hyperactivity, emotional over excitability, hyper reactivity, outbursts of anger or aggressivity, and improved on task behavior. A comprehensive review of the practical uses of clonidine in children and adolescents appeared in the Journal of Child and Adolescent Psychopharmacology (Hunt 1990). Steingard and colleagues (1993) provided further support of a role for clonidine in the treatment of children with ADHD, particularly for those with co morbid tic disorders.

Sleep Disorders

   Wilens and colleagues (1994, 1995) reported benefit in using clonidine for treating sleep disturbances associated with ADHD. This has been an increasingly common use of clonidine in clinical practice.

Managing Side Effects of Cortical Stimulants: Anxiety, Anorexia, Insomnia, Weight Loss, and Rebound Over arousal

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The side effects of the cortical stimulants have been problematic. These typically include decreased appetite (Kalikow, K.T., and Blumencranz, H. 1996), insomnia (Wilens, et al, 1994), potential for increasing motor tics, delayed growth rate, and numerous "rebound" adverse effects. Patient compliance with Ritalin has long been known to be poor (Firestone 1982) in spite of its beneficial clinical effects.   

Aggression

   There is currently no FDA approved medication for the treatment of aggression. Beta blockers such as propranolol have shown some usefulness as reviewed by Connor D.F. (1993). Lithium (Campbell, M., 1995) and Carbamazepine (Silva P.R., 1996) have also been used, among many others. Kemph and colleagues (1993) found clonidine to be significantly effective in reducing symptoms in overly aggressive children. Clonidine may thus hold promise as one of the few medications helpful in treating aggression.

Autism

   Many autistic children have associated problems of inattention, impulsivity, hyperactivity and aggressivity that limit the feasibility or effectiveness of educational and behavioral interventions. Clonidine has been shown to be helpful in reducing these symptoms. Jaselskis and colleagues (1992) examined autistic children with excessive inattention, impulsivity, and hyperactivity and oppositionality. Subjects that had not tolerated or responded to neuroleptics, methylphenidate, or desipramine showed significant improvement with clonidine treatment.

Anxiety Disorders

Generalized Anxiety Disorder (GAD)

   Symptoms of generalized anxiety disorder (GAD) such as palpitations, shortness of breath, sweating, dry mouth, hot flashes, abdominal distress and trouble swallowing may be due to sympathetic autonomic hyperactivity. For some time the Beta receptor blocking agents such as propranolol (Inderal) have
been shown to decrease such symptoms, especially those involving peripheral adrenergic over excitation. Clonidine also shows a muting of the autonomic manifestations of anxiety, and appears to have central effects as well. Clonidine's effect in decreasing anxiety appears independent of its sedative properties. Clonidine has an advantage over the beta blockers in patients with asthma. The alpha agonists do not pose the risk that the beta blockers do in precipitating an asthma attack.

Social Phobia and Selective Mutism

   Seriously symptomatic patients with social phobia suffer from marked anxiety in social situations. It is believed that the anxiety symptoms are likely mediated by an adrenergic hyperactivity. According to Marshall (1993), studies of clonidine efficacy in treating social phobia have had mixed results. This may be due to problems in using the short acting tablet of clonidine which has the potential for producing a rebound anxiety when it suddenly wears off. I have found in my practice that extended release forms of clonidine appear to provide more consistent results in treating social phobias and in cases of selective mutism. Clonidine may also be used in combination with other medications such as the SSRIs (Zoloft), the benzodiazepines (Xanax) chlomipramine (Anafranil) and buspirone (Buspar).
   
Panic Disorder

   Liebowitz and Colleagues (1981) found clonidine to be effective in treating both panic disorder and panic attacks with agoraphobia. Uhde and colleagues (1989) found the antipanic effect did not persist in their study subjects clonidine potential efficacy is based on the possibility that panic disorder is a dysregulation of brain alpha-2 adrenoceptor sensitivity. It is unclear why an initial antipanic effect would not be sustained. The clonidine dose may need to be increased periodically to maintain an antipanic effect. This has been found to be the case when treating many conditions with clonidine and other drugs that are metabolized by the liver. The rapid initial tolerance that appears to slowly "plateau" after a few weeks or months is most likely due to initial increase in liver enzymes that speeds up the clearance of clonidine. Other limitations of clonidine in panic may be due to its rebound hyperarousal often experienced when the short acting oral tablet dose quickly wears off. Rebound hyperarousal could contribute to precipitation's of panics. If this were the case, the extended release formulations of clonidine would be expected to more clearly provide sustained benefit (see section on Clonicel ® in this chapter).

Post-Traumatic Stress Disorder (PTSD)

   Genetic studies by Comings and colleagues (1996) examined Vietnam veterans on an addiction treatment unit who had been exposed to severe combat conditions. They found that a DRD2 variant appeared to confer an increased risk for post traumatic stress disorder (PTSD). The absence of the variant of the gene for making the dopamine receptor was associated with a relative resistance. This suggested that dopamine receptors play a role in PTSD. PTSD symptoms are believed to be also related to noradrenergic hyperarousal, as Nutt (1989) and others (Southwick, S.M., 1993) have explained. Orr SP, and colleagues (1995) found abnormal physiologic responses to loud tones in Vietnam veterans with post traumatic stress disorder.
   Such studies would suggest a potential benefit from treatment with clonidine.    Clonidine has been used to treat Cambodian patients with   post-traumatic stress disorder (Kinzie JD, Leuing P. 1989). Hansenne and colleagues (1991) explored the use of clonidine response as a test in evaluating post-traumatic stress.
   I have found clonidine useful in my practice as an adjunctive treatment to diminish some of the physiologic hyperreactivity that occurs upon exposure to events that trigger PTSD symptoms. I have found similar benefit from clonidine in treating dissociative disorders such as multiple personality disorder, when related to past traumatic events The diminution of a conditioned or sensitized autonomic responsivity serves to make memories that induce fear and panic easier to access and detoxify.

Bipolar Disorder (Manic Depressive Illness)

   Lithium remains the first line and most effective medication for treating bipolar disorder. Other medications found to be effective include Valproate and Tegretol. Based on the catecholamine hypothesis of mood disorders, the manic phase of bipolar disorder may reflect an extreme state of noradrenergic hyperactivity.   A subduing effect on mania by clonidine would certainly support this view. Clonidine has shown some efficacy in treating the manic and mixed phases of bipolar disorder, with minimal side effects (Kontaxakis et al. 1989).

Post Traumatic Brain Injury (TBI)

   There is a broad spectrum of neurophysiological symptoms that characterize the post traumatic brain injury (TBI) syndrome (Gualtieri, 1990).
    Manic syndromes can follow various brain injuries and can greatly complicate rehabilitation and treatment outcome (Starkstein, et al., 1988). Bakchine (1989) and other researchers noted that after brain injury there is an increase in noradrenergic transmission that could be a factor in the precipitation of organic mania. The longer term adverse outcome of an under aroused brain often seen in post traumatic TBI may result from a resetting of brain receptor sensitivity as a consequence of such a massive noradrenergic outpouring immediately following the injury. This may explain why noradrenergic stimulants like the amphetamines have been particularly useful in TBI rehabilitation after the acute stages resolve. Clonidine has also shown usefulness in the rapid reversal of the manic symptoms in patients with focal brain damage, especially after bilateral frontal or right temporoparietal lobe lesions.

   Several studies have documented the effectiveness of clonidine in treating certain types of schizophrenia characterized by problems with arousal. Clonidine's efficacy supports a role for noradrenaline in the etiology of schizophrenia. It is not surprising that paranoid schizophrenia responds the most to treatment with clonidine as this the paranoid state is one involving extremely high noradrenergic states similar to those noted in mania. Clonidine may not be a good antipsychotic per se, but may contribute to stabilizing the over aroused, paranoid aspects of the psychosis. In doing so, clonidine might indirectly enhance the effectiveness of an antipsychotic medication.

Conduct Disorder

   Schvehla found clonidine to be beneficial in a group of prepubertal boys who had dual diagnoses of attention deficit hyperactivity disorder and conduct disorder. These children responded to clonidine after failed trials of conventional drug therapy, consisting mostly of cortical stimulants. (Schvehla T.J., et al., 1987).

Obsessive Compulsive Disorder (OCD)

   Obsessive and compulsive type of symptoms are associated with a wide range of disorders. They can be selectively targeted by SSRIs in combination with other medications such as clonidine (Cohen D.J., et al., 1992). Clonidine may be particularly useful when the OCD symptoms are associated with high arousal states such as excitement, anxiety, reactions to stress.
Hewlet, W.A., and Colleagues (1992) compared the efficacy of chlomipramine, clonazepam, and clonidine in the treatment of obsessive - compulsive disorder.

HIV Encephalopathy

   Cesena reported on the behavioral manifestations in the a case of a 4-year-old child with acquired immunodeficiency syndrome (HIV).   Initial manifestation of central nervous system involvement consisted of sudden onset of impulsivity, hyperactivity, initial insomnia, and aggressive behavior. This clinical picture suggested an initial presentation of HIV-1 encephalopathy. Clonidine was helpful in ameliorating these behaviors (Cesena M, et al., 1995).

Asthma and Allergies

   Lindgren and colleagues (1987). Compared of the effects of clonidine and guanfacine on the histamine liberation from human mast cells and basophiles and on the human bronchial smooth muscle activity. Clonidine, but not guanfacine inhibited the antigen-induced histamine release from human basophiles and mast cell preparations. Clonidine and guanfacine had no effects on the basal bronchial muscle tone. It was suggested that the inhibitory effects of clonidine on allergic reactions and on excitatory nerve transmission in human airways may be useful in the treatment of asthma or allergies.

Migraine

   Clonidine has been used for the treatment of headaches, and for the prevention and reduction of narcotic use in migraine patients (Bredfelt, R.C., et al., 1989).

Narcotic Withdrawal

   Clonidine has been used to diminish the signs and symptoms of morphine, heroin and other narcotic withdrawal (Jasinski, D.R., 1985; Kleber, H.D., et al., 1987; Spencer, L. and Gregory, M., 1989).

Potential Benefits for Prefrontal Cortical Deficits

   Alpha-2 receptor agonists such as clonidine and guanfacine may reduce prefrontal deficits in working memory, executive function or focused attention, with relative sparing of episodic short term memory in patients with Korsakoff's disease, attention deficit disorder or schizophrenia. may benefit from treatment with clonidine and guanfacine. a These agents appear to have little therapeutic value in patients with dementia of the Alzheimer's type (Arnsten A.F., et. al., 1996).   

Basic Pharmacology

Mechanisms of Action

Alpha Receptors

   In the brain, the central noradrenergic receptors can be divided pharmacologically into alpha-1 and alpha-2 subtypes. The alpha-1 are post synaptic receptors, and the alpha-2 are both pre- and post synaptic receptors. Clonidine
activates both subtypes, with preferential activity at the alpha-2 adrenoceptors. Alpha-2 receptors have an auto regulatory function. Their activation appears to have a direct inhibitory action that tends to reduce central noradrenergic activity and to decrease noradrenergic transmission.
   Clonidine was synthesized in the early 1960s. During clinical testing as a topical nasal decongestant, clonidine was found to cause hypertension, sedation and bradycardia in large doses. At much lower doses, clonidine lowered blood pressure in hypertensive patients. The explanation for these effects appears to be that at low doses clonidine acts mostly as an alpha-2 agonist, reducing release of noradrenaline. At high doses, however, it acts as an alpha-1 agonist. Activation of the alpha-1 receptor leads to opposite effects by increasing in the post synaptic effects of noradrenaline.

Locus Coeruleus

   The noradrenergic terminals, most of which originate at the locus coeruleus in the medulla, are widely distributed throughout the brain. Although noradrenergic neurons represent less than 1 percent of the total population of brain neurons, their high collateralization makes each neuron have as many as half a million terminals. Consequently, the importance of the noradrenergic neurons is great in spite of their relatively smaller numbers (Moore 1982).
   Electrophysiological and neurosurgical lesion studies with experimental animals have implicated the ascending dorsal noradrenergic bundle of the locus coeruleus system in cognitive process such as memory, learning and selective attention (Coull J.T., 1994).

Central and Peripheral Autonomic Nervous Systems

   Connections between central autonomic centers, such as the locus coeruleus in the brain, and the peripheral autonomic nervous system in the spine and peripheral nerves contribute to the regulation of the body's heart rate, blood pressure, respiration, as well as the regulation of the brain's arousal and reactivity.
   The lowering of noradrenergic or sympathetic tone with clonidine is beneficial to many disorders involving an autonomic nervous system that is hyper-reactive. In the original use of clonidine for hypertension, lowering sympathetic tone prevented blood pressure from becoming too high.   Arousal is also regulated to a large extent by the central and peripheral autonomic nervous systems, and symptoms of hyperarousal can also respond to clonidine.

Prefrontal Cortex

   Noradrenaline appears to play a crucial role in the cognitive functions associated with the frontal lobes, particularly the prevention of distractibility by irrelevant stimuli. The alpha 2-receptors of the prefrontal cortex appear to be of particular importance in this respect. Affinity for the alpha-2A adrenergic
receptor is associated with improved working memory and attention regulation in the aged primate (Arnsten A.F., et. al., 1996).
   The aged primate brain is prone to profound catecholamine depletion in the prefrontal cortex as well as degeneration of the locus coeruleus. Elderly monkeys show deficits in performance of the delayed response task, which can be reversed by both clonidine, and the alpha-2 agonist guanfacine.
   These results can be explained by an attenuation of the distracting properties of irrelevant stimuli following stimulation of noradrenergic activity. Conversely, distractibility is magnified whenever noradrenergic activity is reduced.
   Similar findings have been reported in studies of healthy humans. The exception to this is when the locus coeruleus is firing in response to stress or when novel stimuli are encountered. By decreasing locus coeruleus firing on such occasions, clonidine counteracts the effects of stress on task performance. Such effects, however, may be beneficial or deleterious. Some amount of stress may improve task performance. Too much, however, can interfere from locus coeruleus overdrive.
   Bob's Mr. arousal machine (see chapter 5), again, provides us with a common example of this mechanism. Bob knows that test performance anxiety gave him that extra "edge" that helped him stay focused. "Before 'Mr. Arousal,' I couldn't seem to pay attention unless I was a little scared," he acknowledges. At times, however, Bob's anxiety got out of control. "At these times I would freeze, lock up, block, become too distractible or even confused.   I couldn't remember things on a test that I knew I had learned. When the test was over I could remember the answers," he laments, "but then it was too late. But Mr. arousal has fixed all that!"
   In real life, where is no Mr. Arousal machine, medications such as clonidine and various anxiolytic medications can be beneficial in decreasing the deleterious effects of excessive performance anxiety.

Pharmacodynamics

   Clonidine is well-absorbed after oral administration. It's bioavailability is nearly 100 percent. The peak plasma concentration and the maximal hypotensive effect are observed in one to three hours after an oral dose. The elimination half-life ranges from six to 24 hours with a mean of about 12 hours. This appears to much shorter in children and adolescents probably due to more rapid hepatic metabolism. About half of an administered dose can be removed unchanged from the urine, and in patients with renal failure the half-life may be increased. There is good correlation between the plasma concentration
of clonidine and its pharmacological effect. The clonidine Transdermal Therapeutic System (Catapres tts) patch provides a constant release rate for a week and takes three to four days to reach steady-state concentrations in plasma. Plasma concentration remains stable for about eight hours following the patch removal, and as it gradually declines, blood pressure will rise.

   In 1995, the public radio network circulated a story about a possible link between the combination of clonidine and methylphenidate and cases of unexplained sudden death in several children. The Food & Drug Administration had received four reports of sudden deaths of children who had taken a clonidine - methylphenidate combination during the previous year (Fenichel 1995).
A review (Popper, 1995) of the four individual cases revealed that other factors (recent anesthesia, a history of fibrosis and heart murmur, apparent multi drug overdose, history of syncope) were sufficient to cause the reported deaths without implicating clonidine.
   The normal rate of sudden unexplained deaths in the general population is estimated as about 1 per 10,000 children yearly (Denfield and Garson 1990). Estimations of the rate of reported sudden unexplained deaths for children on a clonidine-psychostimulant combination are about the same, or 1 per 10,000 children yearly (Swanson et. al., 1995). Because the two rates were essentially the same, there was no basis for concluding that there was an increased risk from being treated with a clonidine-methylphenidate combination. The FDA decided that the available data did not support the theory of an increased rate of sudden unexplained deaths. No further action was deemed to be warranted beyond continued monitoring.
   Despite these conclusions, an unsubstantiated panic rapidly spread by way of newspapers and the NPR Network. There were many unwarranted discontinuations of what had been effective and necessary treatments with clonidine and methylphenidate. This raised ethical questions about what defined responsible journalism (Popper, 1995).
   Cantwell and colleagues (1997) reviewed four cases in which minor adverse reactions were noted in patients treated with clonidine. In two cases, the combination of methylphenidate and clonidine was associated with minor cardiovascular effects and EKG abnormalities, both of which disappeared when the clonidine dose was reduced. In the third case, the patient skipped an evening dose of a clonidine tablet and had an apparent rebound over arousal which
resolved without complications. Such problems with rebound over arousal occur much less frequently with the transdermal clonidine patch and, in my experience, with oral extended release clonidine (Clonicel). The last case concerned a sudden death in a patient who had a history of exercise induced black outs prior to starting clonidine treatment. Clonidine was not determined to have been a contributing factor in his death. These reports, like prior ones, were frightening at first, but on closer examination turned out to be non conclusive.

Risk verses Risk: Finding a Balance

   The other side of the risk equation is rarely discussed. How many lives were saved by the successful management of a potentially hazardous medical condition? This is a number much more difficult to accurately measure or even define. Untreated persons may die in automobile crashes or other accidents from failed vigilance. It has long been appreciated that it is common for untreated people to self medicate. The adverse and even lethal effects of chronic nicotine, caffeine and alcohol Blouin, A.G., et al., 1978)use are well known: lung and a host of other cancers, coronary artery and other heart diseases, sclerosis of the liver, pancreatitis, the list goes on and on.    Marijuana and cocaine and unsupervised stimulant use are also common forms of self medication. Suicides from the complications of failed lives, untreated depressive illnesses, drug misuse, impulsive and risk seeking behaviors all contribute to an unknown rate of death and misery (Loney, J., et al., 1981; Mannuzza, S., et al., 1993). This undetermined rate is rarely considered in risk assessment of a given treatment.
   One example may suffice. A young child patient of mine had lost his mother when he was two and a half years old to a single automobile accident. She was not under the influence of any drug, was driving normally, the weather was fine. He car simply ended up in a ditch for unexplained reasons. This boy's mother had been known as a bubbly, friendly, extrovert. She was always the "life of the party". She was very personable and successful as a pharmaceutical representative. Her friends affectionately teased her, however, about being a "dumb blond" or a "space cadet" because she was forever looking for her keys, purse, or where she parked her car. She was always late, or showed up at the wrong place or at the wrong time. She was a good driver.   When she talked on her car phone, however, she would become so over focused that she would miss turns or exits and get lost. She often found herself in a town different from the one she had intended to drive to. In school she had been a bright student with poor grades and had been diagnosed as having learning disabilities. She was constantly in trouble for socializing too much in class. Her gift of gab and engaging personality
turned out, in the end, to make an important contribution to a successful career that depended on good "people skills".
Why did my young patient lose her to an unexplained automobile crash? No one will ever know for sure. No one ever considered that she may have had a neurobiological disorder that placed her at significantly increased risk for death. Barkley, and colleagues (1993), reported on such driving-related risks and outcomes of attention deficit hyperactivity disorder in adolescents and young adults. More recently a study in New Zealand (Nada-Raja et al., 1997) found that adolescents with ADHD were more likely than their peers to commit driving offenses. Female subjects, in particular, were more likely to be in crashes.
   This is a sad topic to ponder, but important to acknowledge if helpful and necessary medical treatments are to be protected from one-sided arguments about risk assessment. As in all treatment planning, a careful weighing of all potential risks and benefits must be completed in collaboration with the patient, and an informed consent accomplished and documented (Krener P.K., and Mancina, R.A., 1994) (see appendix A).

   This section briefly summarizes my clinical experiences in developing and using an extended-release oral capsule of clonidine, Clonicel.

Problems With Clonidine Tablets: Roller Coaster Effects

   While clonidine has proved to be an extremely powerful and useful medication for a wide variety of conditions, there have been significant problems with the traditionally available preparations (oral tablets and transdermal patches) that have, unfortunately, limited its use. These problems have mostly involved the ease of administration and the control of side effects.
   The beneficial effects of a dose of oral clonidine in children tend to last only 2-3 hours that necessitates the administration of the oral tablets at least 3-4 times per day. Even with this frequent dosage "peak and trough" side effects of sedation and rebound hyperarousal can be problematic. Clonidine's clinical effects appear with its rapid absorption. A sharp peak of effects occurs about one hour after ingestion, and then rapidly falls off. Patients often report transient periods of drowsiness about one hour after taking a dose, and may even fall asleep and nap for 10-15 minutes until this passes. Four or five hours after taking the dose can be a rebound period with hyperactivity,
anxiety, emotional outbursts, and so forth.   If this occurs in the middle of the night there can be nightmares and insomnia.   

  In the original use of clonidine for the control of high blood pressure, rebound effects in the form of sudden rises in blood pressure could be dangerous. Such a rebound could result in middle of the night or early-morning blood pressure surges.   Abrupt discontinuation of high doses of clonidine without tapering can present a hazard for a malignant hypertensive episode. Such adverse blood pressure effects have not been noted, however, in individuals who are normotensive (do not have high blood pressure to begin with).
   Blood pressure does not appear to be significantly effected in normotensive patients. Rare cases of sudden death have not been conclusively attributed to any use of clonidine. The concern has been raised, on theoretical grounds, that the rebound noradrenergic overdrive which may occur with abrupt discontinuance of clonidine may pose risks to patients with undiagnosed cardiac disease. For this reason routine cardiac and blood pressure screening and monitoring is considered prudent until this issue is clarified.

   In my clinical practice, I have used an extended-release oral form of clonidine, Clonicel , that I have had compounded by a local pharmacist. On the basis of my uncontrolled clinical observations in treating over 500 hundred patients, this extended-release formulation appears to be easier to administer, has virtually no side effects of sedation or rebound hyperarousal, and has better patient satisfaction and compliance. The end result is that the percentage of successfully treated clonidine responsive cases has been greatly increased.

   Clonicel has identical properties as clonidine if it were possible to maintain a steady blood level and good patient compliance using the tablets or patch. In other words, it is the lack of peak and trough properties and skin irritation that results in a medication now acceptable to the patient. This results in better compliance that translates ultimately to successful treatment. Every clinician knows that there is no medicine that works well if the patient will not take it. Clonicel's innovation was in providing a delivery system for clonidine that provided the therapeutic effects of clonidine, and yet was easy enough to use and free enough from side effects that patients would actually use it.
   I have used Clonicel, typically in doses ranging from 0.025 mg to 0.3 mg two or three times per day in more than 300 children who were clinically diagnosed to have ADHD. These children were treated in a private practice setting, with assessments of therapeutic effects, adverse effects, and compliance based on the feedback of the children, parents, and teachers (and using some standardized checklists. In most of these children, the medication was used as an adjunct to psychostimulant therapy when residual behavioral symptoms (hyperactivity, impulsivity, aggressivity, or emotional hyper-reactivity) remained problematic. In some cases clonidine was used alone, primarily in hyperactive children who did not tolerate psychostimulant side effects or who had more prominent behavioral than cognitive symptoms.
   Adverse effects of extended release clonidine appeared identical to commercial forms of clonidine, resembling the side effect profile of the clonidine skin patch. Mild sedation was frequently seen but easily managed by decreasing the dose and then gradually increasing as tolerated. The orthostatic effects were of minimal clinical significance. Rebound hyperactivity, rebound hyperarousal, nightmares, and insomnia did not appear to be induced by the extended-release formulation.
   From my observations in using it clinically, Clonicel provides a reliable clinical effect that is maintained for about 8-10 hours permitting a dosing schedule of 2 or 3 times per day. In my patients this has provided beneficial effects as stable and reliable as the transdermal patch but without the problematic side effects of the patch. The sedation and rebound problems of the oral tablets were not noted with Clonicel.

   Clonicel is not currently being manufactured and is not available commercially. In my practice the pharmacist prepares the compounded formula locally, in compliance with a prescription order from the physician, within the scope of lawful compounding practice. Clonidine has, of course, been approved by the Food & Drug Administration for commercial manufacturing, distribution and use in patients under medical care. The pharmacist uses generically manufactured clonidine tablets and pulverizes them into an extremely fine powder. This powder is mixed with a methyl cellulose extended release polymer specifically, specifically hydroxypropylmethylcellulose (HPMC) of a specific molecular weight and viscosity. This particular polymer has broad clearance from the FDA as a direct food additive. The compounded clonidine is then placed into a gelatin capsule.

* Clonicel ® is the trademark for the patented technology of oral extended release forms of clonidine. Its preparations and/or use of the name Clonicel ® is restricted to licensed parties in accordance with specific standards of formulation and quality control. There has been no fee for licensure. Parties skilled in the practice of compounding and who are interested in licensure may contact the author.