Yohimbine-induced withdrawal and anxiety symptoms in opioid-dependent patients

Abstract

Background: Alteration in noradrenergic regulation as well as alteration in the hypothalamic—pituitary—adrenal (HPA) axis have been associated with opioid dependence and acute abstinence symptoms.

Methods: This double-blind, placebo-controlled study evaluated subjective, physiologic, and biochemical responses to yohimbine (.4 mg/kg, IV) in eight patients receiving methadone and compared results to those from a pool of nine healthy volunteers. All subjects were compared for panic anxiety symptom scale (PASS) scores, systolic and diastolic blood pressure, heart rate, plasma 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol.

Results: Yohimbine elicited objective and subjective opioid withdrawal and elevated craving for opioid drugs in methadone patients. Significant yohimbine effects were seen across the combined subject group for PASS, physiologic measures, MHPG, and cortisol. Methadone patients had lower baseline MHPG levels. Methadone group interactions with yohimbine were seen for systolic blood pressure and cortisol levels.

Conclusions: Methadone-maintained patients are sensitive to the postsynaptic effects of noradrenergic-facilitating medications, experiencing greater physiologic and psychological symptoms, including an increase in craving. The effect on cortisol supports the above conclusion and is consistent with HPA axis perturbation in opioid dependence as reported in other studies and extends these observations to stable methadone-maintained patients. Medications that increase synaptic noradrenaline should be used with care in opioid-dependent patients.

Introduction

Alteration in noradrenergic function as a result of chronic exposure to opioid agonists is well known. Increased noradrenergic activity has been established as a major biochemical component of withdrawal symptoms during opioid abstinence. The clinical significance of noradrenergic changes in patients who are stable in opioid substitution treatment has received less attention, and indeed evidence has been reported supporting normalization of most biochemical and endocrine measures after the first 2 months in maintenance patients (Kreek et al 1983). In addition to noradrenergic system alterations, hypothalamic—pituitary—adrenal (HPA) axis alterations have also been proposed to play a role in opioid dependence. For instance, several studies have also shown a rise in cortisol and adrenocorticotropic hormone (ACTH) in response to administration of opioid antagonists in opioid-dependent patients Judd et al 1981, Naber et al 1981, Volavka et al 1978, Volavka et al 1979. Conversely, when opioid agonists are administered acutely to nondependent subjects, cortisol and ACTH levels are known to decrease Cushman and Kreek 1974, Kreek and Hartman 1982. Recently, as more attention has been focused on HPA axis abnormalities in addiction, there is increasing evidence (reviewed by Kreek and Koob 1998), that these measures could be an important index of opioid dependence.

Although methadone-maintained opioid-dependent patients are considered to be stable with respect to most psychological and physiologic symptoms, symptoms of anxiety are widespread in this population. In a survey of 533 opioid addicts using Research Diagnostic Criteria (RDC; Spitzer et al 1978), researchers (Rounsaville et al 1982) found a 13.2% lifetime prevalence of anxiety disorders for men and a 25.4% lifetime prevalence for women, compared to a 14.6% prevalence for anxiety in the general population according to the ECA (Regier et al 1988). The National Comorbidity Study also reported increased risk of anxiety disorders in substance abusers (odds ratio ranging from 2.2 [phobia] to 3.2 [for posttraumatic stress disorder]) compared to nonsubstance abusers (Kessler et al 1994). In addition, pronounced symptoms of anxiety are seen during acute withdrawal from opioids and during opioid abstinence (Himmelsbach 1988, Lasagna et al 1955, Martin and Jasinski 1969; review by Satel et al 1993).

Noradrenergic mechanisms are known to be fundamental to opioid withdrawal as well as anxiety symptoms Gold et al 1980, Gold et al 1982. Much animal and human research has documented the importance of the interaction between brain noradrenergic and opioid systems Aghajanian 1978, Bird and Kuhar 1977, Hamburg and Tallman 1981, Korf et al 1974, Pepper and Henderson 1980. This research has lead to an important advance, the discovery that the imidazoline antihypertensive, clonidine, an agonist at presynaptic alpha₂ receptors that reduces the release of norepinephrine from locus coeruleus neurons, effectively reduces many opioid withdrawal symptoms Charney et al 1982, Gold et al 1978, Gold et al 1980, Washton and Resnick 1980, Washton and Resnick 1981.

Because clonidine decreases central noradrenergic activity and opioid withdrawal, yohimbine, an alpha₂ adrenergic antagonist, which stimulates the release of norepinephrine from locus coeruleus neurons, might be expected to induce opioid withdrawal-like symptoms. A brief preliminary study reported opioid withdrawal symptoms in methadone patients after acute oral administration of .4 mg/kg yohimbine (Lannon et al 1986). This report did not characterize the clinical response in detail and did not directly address the biochemical or endocrine consequences.

The present study examined the effect of yohimbine on opioid withdrawal and anxiety symptoms as well as concomitant changes in physiologic and biochemical indicators of noradrenergic and HPA axis functions. We report a blinded, placebo-controlled study of the effect of yohimbine in methadone patients and compare these results to responses of normal subjects with respect to anxiety, physiologic, and biochemical measures.