Methylphenidate Clonidine

Reports of Sudden Death with Combined Clonidine-Methylphenidate Treatment... 

Controlled trials of TCA therapy for comorbid ADHD and chronic tics or Tourette s disorder show significant improvement in inattentive and hyperactive/impulsive symptoms without worsening of tics. In one study, both tics and symptoms of ADHD improved. TCAs offer an alternative to clonidine or combined clonidine/ methylphenidate therapy that may be more effective for some patients. 

The proposed mechanism of ADHD pharmacotherapy is to modulate neurotransmitters in order to improve academic and social functioning. Pharmacologic therapy can be divided into two categories stimulants and non-stimulants. Stimulant medications include methylphenidate, dexmethylphenidate, amphetamine salts, and dextroamphetamine, whereas non-stimulant medications include atomoxetine, tricyclic antidepressants (e.g., imipramine), clonidine, guanfacine, and bupropion. 

Drugs that may be affected by dexmethylphenidate or racemic methylphenidate include antihypertensive agents, pressor agents, coumarin anticoagulants, anticonvulsants, tricyclic antidepressants, selective serotonin reuptake inhibitors, and clonidine. 

Antacids/Acid suppressants (Ritalin LA only) Because the modified release characteristics of Ritalin LA capsules are pH dependent, the coadministration of antacids or acid suppressants could alter the release of methylphenidate. Clonidine Serious adverse reactions have been reported in concomitant use with clonidine, although no causality for the combination has been established. 

Swanson, J.M., Connor, D.E, and Cantwell, D. (1999b) Combining methylphenidate and clonidine ill-advised. J Am Acad Child Adolesc Psychiatry 38 617-619. 

Some authors have questioned whether there is sufficient efficacy and safety data to support widespread use of the a2-adrenergic agonists (Cantwell et al., 1997), a position which intensified following the report of several sudden deaths of children who were medicated with clonidine and methylphenidate in combination (Popper, 1995). Although the FDA could not establish a causal link between the medications and these catastrophic outcomes, clearly more research is needed. At the same time, interest at the national level in establishing a more extensive scientific database to support the use of previously off-label prescription patterns, and interest on the part of industry to obtain FDA approval for new indications, suggests that larger... 

Since the mid-1990 s, there have been no further reports of seriouse methylphenidate-clonidine toxicity, possibly owing to less frequent use of this medication combination. However, more recent studies have ques-... 

Connor, D.F., Barkley, R.A., and Davis, H.T (2000) A pilot study of methylphenidate, clonidine, or the combination in ADHD comorbid with aggressive oppositional defiant or conduct disorder. Clin Pediatr 39 15-25. 

Fenichel, R.R. (1995) Combining methylphenidate and clonidine the role of post-marketing surveillance. / Child Adolesc Psychophar-macol, 5 155-156. 

Brown, T.E. and Gammon, G.D. (1992) ADHD-associated difficulties falling asleep and awakening clonidine and methylphenidate treatments. In Newcorn, J., ed. Scientific Proceedings of the Annual Meeting American Academy of Child and Adolescent Psychiatry. Washington, DC Washington, DC American Academy of Child and Adolescent Psychiatry p. 76. 

Hunt, R.D. (1987). Treatment effects of oral and transdermal clonidine in relation to methylphenidate An open pilot study in ADD-H. Psychopharmacol Bull 23 111-114. 

Wilens, T.E. and Spencer, T.J. (1999) Combining methylphenidate and clonidine a clinically sound medication option. J Am Child Adolesc Psychiatry 38 614—622. 

Gadow et al. (1995), however, found no increase in tics in a placebo-controlled trial of methylphenidate in children with ADHD and a tic disorder. Other trials of stimulants in such children have found little or no average increase in tic severity scores, but clinically significant increases of tics in a handful of subjects severe enough to prompt discontinuation of the stimulant (Castellanos et al., 1997 Law and Schachar, 1999) or to require addition of a medication to control their tic symptoms (Gadow et al., 1999). A multicenter, doubleblind, placebo-controlled, parallel group study of methylphenidate and clonidine, used alone or in combination in 136 children with ADHD and a comorbid... 

Loof et al. (1995) reported the use of carbamazepine (300-1200 mg/day, serum levels 10-11.5 pg/mL) in 28 children and adolescents with sexual abuse histories. By treatment end, 22 of 28 patients were asymptomatic of PTSD. The remaining six were significantly improved in all PTSD symptoms except for continued abuse-related nightmares. Half of this cohort had com-orbid ADHD, depression, ODD or polysubstance abuse and were treated with concomitant medications, e.g., methylphenidate, clonidine, sertraline, fluoxetine, or imipramine. 

A number of clinical trials have found clonidine to be superior to placebo in treating ADHD ( 101, 102,103 and 104). However, these studies were generally not as methodologically rigorous as those with either psychostimulants or antidepressants. Clonidine has been used as monodrug therapy and in combination with methylphenidate. Hunt (101) did a crossover study of clonidine alone, methylphenidate alone, and the combination in 25 children with ADHD and conduct disorder. 

The combination was reported to be superior to either agent alone in reducing parent ratings of conduct problems. However, the combination has never been tested in children with ADHD alone for the core symptoms of hyperactivity, inattention, and impulsivity. There is also concern about the safety of this combination because there have been four deaths in children (105). However, there were enough complicating factors present in each of these cases that no conclusions could be drawn about the role of methylphenidate and clonidine in these deaths. For these reasons, the use of clonidine for the treatment of ADHD should be tried only after trials of more than one psychostimulant and after an antidepressant trial. 

Injection of botulinum toxin A at the site of problematic tics is sometimes helpful. Treatment of any associated attention deficit disorder (eg, with clonidine patch, guanfacine, pemoline, methylphenidate, or dextroamphetamine) or obsessive-compulsive disorder (selective serotonin reuptake inhibitors or clomipramine) may be required. Bilateral thalamic stimulation is sometimes worthwhile in otherwise intractable cases. 

In this chapter, we have looked at two topics in cognitive enhancement attention and memory. We have first reviewed the role of dopamine and norepinephrine/ noradrenaline in the neuropharmacology of attention, and then the syndrome of attention deficit disorder as a common problem associated with a disorder of attention. We then discussed the use of stimulants for improving attention, primarily in attention deficit disorder, and reviewed the pharmacological mechanisms of action of methylphenidate, d and 1 amphetamine, pemoline, and secondary therapies such as clonidine and guanfacine. 

Clonidine hydrochloride (Catapres), carbamazepine (Tegretol), and methylphenidate (Ritalin) are occasionally useful in intractable cases of migraine. Cyproheptadine (Periactin) may be effective in adults with migraine it is of considerable importance in the treatment of childhood migraine, and many consider it to be the drug of first choice. Dosages range from 4 to 3 mg, three to four times a day, in adults and 4 mg, two to three times a day, in children. 

Popper CW. Combining methylphenidate and clonidine pharmacologic questions and news reprots about suddent death. J Child Adol Psychopharmacol. 1995 5 157. 

Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450 2D6 inhibitors may increase TCA concentrations Cimetidine may increase plasma concentrations of TCAs and cause anticholinergic symptoms Phenothiazines or haloperidol may raise TCA blood concentrations May alter effects of antihypertensive drugs may inhibit hypotensive effects of clonidine Use of TCAs with sympathomimetic agents may increase sympathetic activity Methylphenidate may inhibit metabolism of TCAs... 

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