Effect of intravenous magnesium sulphate in reducing irritability and restlessness in pure and polysubstance opiate detoxification

Abstract

The aim of this double-blind, placebo-controlled study was to evaluate the efficacy of intravenous magnesium sulphate (MgSO₄) on the need for chlormethiazole in pure or polysubstance opiate detoxification. Forty-one inpatients suffering from pure and polysubstance opiate dependence were treated with morphine sulphate pentahydrate in a gradual detoxification program. Morphine reduction took about 11 days. Additionally, 5% MgSO₄ was administered intravenously to the intervention group (Mg group, n = 22) over 24 h by perfusor (150–200 mg MgSO₄/h; plasma level of 2.36 ± 0.29 mmol/l), whereas NaCl 0.9% was intravenously administered in the placebo group (n = 19). In case of withdrawal symptoms (irritability, restlessness, and insomnia), patients received chlormethiazole p.o. Our hypothesis that the need for chlormethiazole would be decreased by adjunctive administration of Mg was not confirmed in our study population (2180 mg/day in the Mg group vs. 2360 mg/day in the placebo group). There was neither a difference in the quantity of chlormethiazole required nor a difference in the severity of withdrawal symptoms measured with the Wang scale between the two comparison groups. We observed that calcium plasma levels decreased and phosphate plasma levels increased significantly during intravenous therapy with Mg. Despite promising pilot studies, the administration of Mg did not enable a dose reduction of tranquilizing medication (chlormethiazole) in pure and polysubstance opiate detoxification

Introduction

Patients who undergo opiate detoxification develop intense physical discomfort (muscle aching, cramping, and vomiting), irritability, restlessness, and insomnia. Withdrawal symptoms can be reduced by α₂-adrenergic agonists (Gowing et al., 2002) or by sedative medication, including sleep-inducing neuroleptics, antidepressants, and tranquilizers. These substances have a risk of substantial side effects such as extrapyramidal symptoms, hypotonia and sometimes confusion; moreover, tranquilizers, per se, have an addictive effect (tolerance phenomenon).

We were interested in identifying an alternative treatment with fewer adverse effects for patients undergoing opioid detoxification and chose intravenous (i.v.) treatment with magnesium (Mg) sulphate based on its muscle-relaxing and sedative effect (Miller-Reiter et al., 1995, Heiden et al., 1997). Hypermagnesemia is described to have a depressive effect on the central nervous system. The sedative and antinociceptive effect of Mg has proved to be useful in anaesthesia (James, 1992, Tramèr et al., 1996) and as an adjunctive therapy in the clinical management of severe manic agitation (Heiden et al., 1999). Parenteral Mg is recommended in the management of preeclampsia, myocardial infarction, and selected cardiac arrhythmias, and also has been suggested for the treatment of asthma bronchiale and tetanus (McLean, 1994, Frakes and Richardson, 1997, Attygalle and Rodrigo, 1997, Reddy, 2002, Silverman et al., 2002, Shechter, 2003, Lee and O'Connell, 2004).

Mg acts as an essential co-factor in diverse enzyme reactions of the energy metabolism, phosphate transfer, muscle contractility and neurochemical transmission (Garfinkel and Garfinkel, 1985). Mg is directly involved in the regulation of the intracellular and extracellular homeostasis of potassium (K) and calcium (Ca). It has been referred to as a physiological Ca channel blocker, in the sense that processes activated or stimulated by Ca ions may be deactivated or inhibited by Mg ions (Iseri and French, 1984). Ca channel blockers have illustrated antinociceptive effects (Miranda et al., 1992, Wong et al., 1994) and can strengthen acute central effects of opiates in animals (Hoffmeister and Tettenborn, 1986, Lux et al., 1988). Santillán et al. (1994) observed that Ca channel blockers enhance morphine analgesia in cancer patients with chronic pain. Although the role of Mg in neuronal function is not completely understood, it has been shown that Mg is able to block Ca influx and to antagonize noncompetitively N-methyl-d-aspartate (NMDA) channels (Lipton and Rosenberg, 1994). These findings have prompted further investigations of Mg as an analgesic agent. When Mg sulphate (MgSO₄) alone was intrathecally administered in animals, no analgesic effect was observed (McCarthy et al., 1998), but spinal analgesia and delay of morphine tolerance were illustrated when MgSO₄ was co-administered with morphine intrathecally (McCarthy et al., 1998, Kroin et al., 2000). Bregan et al. (2002) showed in animals that Mg amplifies the analgesic effect of low-dose morphine in conditions of sustained pain.

MgSO₄ decreases the postoperative need for opiate medication in patients with severe pain, which indicates a potentiating effect of Mg on opioid analgesia (Tramèr et al., 1996, Koinig et al., 1998). However, this effect has not always been observed in clinical studies (Wilder-Smith et al., 1997).

Examinations of the sleep-electroencephalogram (EEG) and of endocrine systems point to the involvement of the limbic–hypothalamus–pituitary–adrenocortical axis as Mg affects all elements of this system. Mg has the property to suppress hippocampal kindling, to reduce the release of adrenocorticotropic hormone (ACTH), and to affect adrenocortical sensitivity to ACTH. The role of Mg in the central nervous system could be mediated via the NMDA-antagonistic, gamma-aminobutyric acid-agonistic or angiotensin II-antagonistic property of this ion (Murck, 2002).

The recent findings on the antinociceptive, sedative, and muscle-relaxing effects of Mg prompted us to investigate i.v. MgSO₄ as an adjunctive drug to the standard therapy in clinical management of opiate detoxification by performing a double-blind placebo-controlled study. We hypothesized that i.v. Mg would reduce the need for chlormethiazole in opiate and polysubstance detoxification.