Methylphenidate with clonidine

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... 

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. 

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. 

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

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. 

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. 

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. 

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... 

Medications play an important part in the treatment of ADD. Stimulants are the mainstay of the treatment of ADD methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and pemoline (Cylert). These differ in their half-lives, with Ritalin having the shortest and Cylert the longest. A warning has recently been issued about Cylert because of reports of sometimes fatal liver toxicity. Thus, it is recommended that it be used only if methylphenidate and dextroamphetamine are ineffective. There is individual variability in resporise, so that a person who does not respond to one may respond well to another. Other medications can also be effective in the treatment of ADD and may be useful, especially in residual ADD, where substance abuse may be an issue. These include tricyclic antidepressants (especially desipramine and imi-pramine) SSRIs, bupropion, venlafaxine, and clonidine. There are reports of antipsy-chotics and lithium being helpful in selected cases, as well. 

The most common side effect of clonidine is dose-dependent sedation that usually subsides after 2 to 3 weeks of therapy. Of concern are reports of bradycardia, rebound hypertension, heart block, and sudden death. Four children have died on the combination of methylphenidate and clonidine however, complicating factors make it impossible to link the drug combination directly with the cause of death. Of 10,060 children exposed to clonidine and assessed by a poison control center over a 7-year period, moderate (19%) to major (2%) toxic effects (bradycardia, hypotension, and respiratory depression) including one death were reported. Overdoses, concurrent clonidine and stimulant administration, as well as missed doses of clonidine aU add to the risk of adverse cardiovascular events. Similar adverse-effect concerns apply to treatment with guanfacine, although its U2a selectivity may result in less sedation and hypotension than clonidine. ... 

Pharmacotherapy with stimulants increases dopaminergic and noradrenergic activity, which has the potential to aggravate or precipitate tics. One study examined the comparative effects of methylphenidate and dextroamphetamine on tics in children and found the majority experienced improvement in ADHD symptoms with acceptable effects on tics. Methylphenidate was better tolerated than dextroamphetamine. Another double-blind placebo-controlled trial compared methylphenidate or clonidine monotherapy to combination methylphenidate and clonidine in patients with ADHD and Tourette s disorder. Combination therapy demonstrated the greatest benefit in reducing symptoms of ADHD and tics (p <0.0001). Clonidine appeared most helpful for impulsivity and hyperactivity, while methylphenidate was most helpful for inattention. All treatments were well tolerated. 

Much publicised fears about the serious consequences of using methylphenidate with clonidine appear to be unfounded. There is limited evidence to suggest that concurrent use can be both safe and effective. 

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