Treating ADHD in Prison: Focus on Alpha-2 Agonists (Clonidine and Guanfacine)

Stimulants

The stimulant medications, which are so helpful for childhood ADHD, can also be helpful for adults with similar symptoms.⁸ However, most prison inmates have a history of substance abuse,⁹ making prescribing a stimulant in prison problematic. A protocol for prescribing stimulants in prison inmates was presented by Appelbaum.¹⁰ That article and the commentary by Burns¹¹ discussed the complexity of prescribing stimulants in prison, including feigning of symptoms to obtain stimulants. Stimulants can be a valuable commodity in prison; inmates are known to abuse, hoard, and sell medicines much less “attractive” than stimulants (e.g., antidepressants and antipsychotics).¹²

Also, although stimulants are helpful for improving concentration and reducing motor hyperactivity in children, it is less clear that they are helpful for the symptoms likely to be most problematic in adult prison inmates (e.g., impulsive aggression). For example, Connor et al.¹³ suggested in a review that patients with ADHD (<18 years old) with concomitant oppositional defiant disorder (i.e., with defiant and aggressive symptoms) do not respond as well to stimulants as do patients with ADHD alone. So the risks involved with prescribing stimulants in prison may generally outweigh the potential benefits.

Atomoxetine

Atomoxetine is a nonstimulant that has been found to be useful in treating ADHD in children and adults.¹⁴ A comprehensive review by Garnock-Jones and Keating¹⁵ suggests that it may not be as effective overall as sustained-release stimulants, but it is better than a placebo, and may be superior to stimulants in some aspects of quality of life (because of different side effects). Their review also suggested that atomoxetine is as effective for the impulsivity of ADHD as it is for the impaired concentration (and that atomoxetine may be particularly useful for patients with comorbid anxiety). However, in another review, Patel and Barzman¹⁶ concluded that atomoxetine is better at improving concentration than at improving impulsivity, excitability, and aggressiveness. Polzer et al.,¹⁷ presented data indicating that atomoxetine may actually increase irritability and aggression; but Pappadopulos et al.,¹⁸ in a meta-analysis, found reduced aggressiveness in children with ADHD who were prescribed atomoxetine (although methylphenidate reduced aggression more). Bangs et al.¹⁹ did not find that atomoxetine consistently reduced symptoms of oppositional defiant disorder (ODD), although it reduced ADHD symptoms.

History

Clonidine has an interesting history. It (and other α2 agonists) stimulates inhibitory presynaptic norepinephrine receptors in the locus ceruleus, reducing norepinephrine activity; this was thought to explain its efficacy for its first approved use, to reduce blood pressure.¹⁴ Because it reduces norepinephrine activity, it was reasonable to think that clonidine might be of benefit for anxiety disorders (given the role of norepinephrine in the fight-or-flight response), and some small studies found it to be of some benefit for anxiety (e.g., Hoehn-Saric et al.²⁰), but approval for this indication was never pursued. Clonidine has also been used to reduce symptoms of opiate withdrawal (presumably the mechanism also involves its norepinephrine-reducing effect²¹). Clonidine and guanfacine may also be helpful for posttraumatic stress disorder (PTSD)^21,–,23 (which is a common comorbid diagnosis in prison²⁴). Of note, use of α agonists for PTSD was tried partly because of the similarity of some symptoms of opiate withdrawal and PTSD.²¹

Immediate-Release Alpha-2 Agonists for ADHD

Clonidine was first used for ADHD (in the mid-1980s) because it had been used for tics and Tourette's syndrome. Some children with tics also have symptoms of ADHD, and it has been noted to be helpful for these symptoms. Several encouraging studies (mostly small and investigator initiated) reporting evidence of efficacy in children with ADHD (with and without Tourette's) were then conducted with clonidine²⁵ and later with guanfacine.²⁶ A 1999 review²⁷ of studies involving clonidine concluded that clonidine alone reduces the core symptoms of ADHD, but with a smaller treatment effect than that obtained with stimulants.

Interest in standard (now known as immediate-release (IR)) clonidine and guanfacine subsequently waned, apparently because of the loss of patent protection for these drugs. There was no financial incentive to conduct the large studies needed for U.S. Food and Drug Administration (FDA) approval (for a new indication: ADHD). The combination of stimulants and IR clonidine has also been studied relatively little.^28,29 However, Palumbo et al.³⁰ conducted a study comparing clonidine, methylphenidate, the combination (both medications), and placebo in 122 children with ADHD. The results, consistent with those in the literature, showed that clonidine was somewhat beneficial, but was not as effective as methylphenidate.

Extended Release

Once extended-release (ER) forms of these drugs (with new patent protection) were developed, interest and funding revived. Both ER clonidine and ER guanfacine have been studied, have been found to be helpful for ADHD in children and adolescents, and are FDA approved for this indication. The available studies indicate benefit for all of the cardinal symptoms of ADHD, including impaired concentration, hyperactivity, excitability, and impulsivity (Hirota et al.³¹). The ER form of clonidine now has a generic equivalent, but the ER form of guanfacine still has patent protection.

Studies and reviews demonstrating the benefit of the ER forms of clonidine include Jain et al.,³² who reported benefit from clonidine ER in pediatric patients with ADHD; Kollins et al.,³³ who reported that clonidine ER can be helpful if added to a stimulant for children and adolescents who have only a partial response to stimulants; and Croxtall.³⁴ Faraone et al.,³⁵ and Bukstein and Head³⁶ concisely reviewed the use of guanfacine ER for ADHD in children and adolescents, concluded that it too is useful. A recent meta-analysis³¹ attempting to compare benefit from α2 agonists with other medication options (this type of meta-analysis, inherently, is of uncertain validity) reported overall evidence of benefit, comparable with atomoxetine, but not as much as with stimulants.

The studies of α2 agonists for ADHD, in both the IR and ER forms, have mainly been performed in children and adolescents. None is FDA approved for adults, but it is generally true that drugs found to be useful for children and adolescents, at least for psychiatric conditions (including ADHD), are also helpful for adults. So it is not unreasonable to think that studies in younger individuals are also relevant to adults.

Alpha-2 Agonists for ADHD With Aggressive and Oppositional Symptoms

Of particular relevance to a prison population, several researchers have looked specifically at the benefit from α2 agonists in patients with ADHD and concomitant aggressive and oppositional symptoms. Hazell and Stuart³⁷ reviewed several open-label studies and reported on a double-blind study involving 67 children (ages 6–14 years) taking stimulants for ADHD, who also were aggressive and had a concomitant diagnosis of either conduct disorder or ODD. Children were continued on stimulants and were randomized to clonidine or placebo. Results showed significant benefit from clonidine (compared with placebo) on ratings of conduct disorder symptoms. These were children, and all were receiving stimulants, but it suggests that clonidine would be particularly helpful in patients with ADHD and concomitant symptoms of conduct disorder or ODD. In a later review, Hazell³⁸ concluded that clonidine can alleviate the ODD component in combined ADHD/ODD, and the combination of a stimulant with an α2 agonist has been presented in several practice guidelines (e.g., American Academy of Child and Adolescent Psychiatry³⁹). Patel and Barzman¹⁶ reviewed the pharmacology of pediatric ADHD and associated aggression and indicated a need for future research, but also concluded that α2 agonists can reduce irritability and aggressiveness in children with ADHD. Hirota et al.³¹ reached similar conclusions. The one large (n = 217) multicenter study of α2 agonists for ADHD with associated aggression (with ODD) was funded by Shire Pharmaceuticals (which produces ER guanfacine).⁴⁰ It reported ER guanfacine to be significantly better than placebo for overall ADHD symptoms and specifically better for oppositional symptoms in children (ages, 6–12 years) who had ADHD and oppositional symptoms (the children were not receiving concomitant stimulants).

Mechanism of Action: Alpha-2 Subtypes

Both clonidine and guanfacine are α2 agonists. Three α2 subtypes have now been identified⁴¹: 2A, 2B, and 2C. Guanfacine is more selective for the 2A subtype; clonidine binds equally to all three subtypes. Whether this is relevant to a benefit in ADHD is not altogether clear, as noted by Sallee et al.⁴² in a review. Several papers (e.g., Arnsten⁴³) focusing on the importance of the α2A receptor acknowledged support from Shire and reported the advantages of guanfacine (and the advantages of the ER form compared with the IR one).

Historically, when α2 receptors were considered to be primarily agonists of presynaptic receptors on norepinephrine (NE) neurons (inhibiting NE release), it was hard to understand why α agonists would help patients with ADHD, given that other medications for ADHD (e.g., stimulants) increase norepinephrine (and dopamine) activity. The discovery of postsynaptic α2A receptors in the prefrontal cortex⁴³ provided a better theoretical rationale for α2 agonist benefit in ADHD. A genetic study⁴⁴ reported an association between the gene for α2C receptors and ADHD. Despite the theories, it remains unclear how these medications work in alleviating ADHD, and there is no significant evidence that guanfacine is better than clonidine. (The Hirota et al.³¹ meta-analysis, though not based on head-to-head comparisons, did not suggest differences in efficacy between the two drugs.)

Clonidine or Guanfacine: Other Considerations

Guanfacine has a somewhat longer half-life (16 hours versus 12 hours), making a once-daily dosage more feasible, although (as discussed below) a twice-daily dosage may be preferable if using either IR form, to reduce peak plasma levels. Guanfacine has a greater risk of interactions with other medications, specifically with drugs that inhibit or induce 3A4 activity. With either drug, blood pressure should be monitored, especially if related symptoms (e.g., dizziness) occur.

In some respects, it would not be difficult to determine whether guanfacine is better than clonidine. A relatively small inexpensive crossover study might clarify the question, but no funding source seems to be motivated to conduct such a study.

Pharmacokinetics

FDA-approved labeling¹⁴ focuses on the difference in maximum plasma levels (C_max) after a single dose of the ER form versus a single dose of the IR form. For guanfacine, for example, the peak level with the ER form is only about 40 percent of the peak with the IR form. Both types are recommended for once-daily dosage,¹⁴ but if the dose of the IR is divided in half, given as twice-daily dosage, the peak plasma level of the IR (after a single dose) would be reduced by about 50 percent, close to the peak level with the ER.

In addition, the difference in peak plasma level (between IR and ER) is much less at steady state, after multiple doses (steady state occurs after approximately five half-lives). If, at steady state, IR guanfacine is given twice a day (i.e., the dosage interval (12 hours) is about three-quarters of the half-life), the peak plasma level would be more than twice the peak plasma level after a single dose. (These estimates are based largely on information in Dhillon and Gill⁴⁵). In other words, the peak blood level at steady state is about half from the latest dose and half from accumulated guanfacine in the body. The difference in peak plasma level between the IR and ER forms of the medicine would therefore be reduced proportionately, by about half.

Thus, at steady state, a twice-daily dosage of IR guanfacine is likely to result in plasma levels not much different from a once-daily dosage of the ER (perhaps even within the 15% range which would be allowed for a generic). Also relevant, the bioavailability of the ER (the total amount of guanfacine absorbed) is less than that of the IR (only 58% as much, per FDA labeling¹⁴). Possibly related to this, FDA labeling¹⁴ for immediate-release guanfacine suggests that doses above 3 mg are rarely more helpful (for hypertension), although for the ER (used for ADHD), doses of up to 4 mg are suggested. So 1 to 1.5 mg of IR guanfacine, given twice-daily, could reasonably be expected to be comparable with 3 to 4 mg of the ER form.

In the case of clonidine, both the IR and the ER are recommended for a twice-daily dosage. As with guanfacine, the half-life is about the same for both dosage forms (about 12 hours), but the C_max is lower (of course) with the ER (∼50% lower, after a single dose). Again, at steady state, the percentage difference between C_max for the IR and the ER would be considerably less than the difference after a single dose. Also similar to guanfacine, the total amount of medication absorbed is greater for the IR form than for the ER form. (The bioavailability of the ER form is about 25% less.) ER clonidine has been used in amounts of only 0.4 mg per day for ADHD; the dosage for the IR form, which was approved for hypertension, was given (FDA labeling¹⁴) as generally 0.2 to 0.6 mg per day, but it was noted that dosages of up to 2.4 mg per day have been used (for hypertension). Thus (similar to the situation with guanfacine), it seems likely that generic IR clonidine, given up to 0.3 to 0.4 mg per day in two or even three doses, would be comparable with the ER form.

Again, it should be noted that studies of the ER forms for ADHD have been conducted in children and adolescents, whereas studies for hypertension with the IR forms were, of course, conducted in adults. It is reasonable to think that giving adults with ADHD doses comparable to those used in children with ADHD would be well tolerated (perhaps adults could take higher doses, but these have not been studied sufficiently).

IR versus ER: Other Considerations

One advantage of the IR generic forms of these medications is that they are less expensive. As of 2014, the ER forms cost up to 30 times more than the IR forms. Cost may be a reasonable and relevant concern.

There are, of course, physicians who feel more comfortable prescribing forms of drugs that are FDA approved for a particular indication. One might argue that physicians should prescribe based on the knowledge they have of drugs, including pharmacokinetics, and that for drugs with relatively long half-lives, there is little reason to think that the ER forms are clearly preferable.