Journal of Psychosocial Nursing and Mental Health Services

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Psychopharmacology 

Potential Adverse Effects of Discontinuing Psychotropic Drugs--Part 4: Benzodiazepine, Glutamate, Opioid, and Stimulant Drugs

Robert H. Howland, MD

Abstract

For nurses in clinical practice, understanding the pharmacology of drugs their patients take is relevant to understanding their therapeutic uses, side effect profiles, and adverse discontinuation effects. In this article, the last of a four-part series, the discontinuation effects of the following psychotropic drugs are described: benzodiazepine drugs (which have hypnotic, anti-anxiety, and anticonvulsant effects), non-benzodiazepine drugs (used for insomnia), glutamate-modulating drugs, opioid receptor agonist drugs (used as analgesics for the treatment of various pain conditions), and stimulant drugs. Serious adverse effects are likely to occur only after abrupt discontinuation of benzodiazepine drugs, and they should almost always be tapered. Prominent discontinuation effects are seen with opioid and stimulant drugs, but these are usually not serious. Tapering medication, rather than abruptly stopping them, can avoid or minimize the potential adverse discontinuation effects associated with most psychotropic drugs.

Abstract

For nurses in clinical practice, understanding the pharmacology of drugs their patients take is relevant to understanding their therapeutic uses, side effect profiles, and adverse discontinuation effects. In this article, the last of a four-part series, the discontinuation effects of the following psychotropic drugs are described: benzodiazepine drugs (which have hypnotic, anti-anxiety, and anticonvulsant effects), non-benzodiazepine drugs (used for insomnia), glutamate-modulating drugs, opioid receptor agonist drugs (used as analgesics for the treatment of various pain conditions), and stimulant drugs. Serious adverse effects are likely to occur only after abrupt discontinuation of benzodiazepine drugs, and they should almost always be tapered. Prominent discontinuation effects are seen with opioid and stimulant drugs, but these are usually not serious. Tapering medication, rather than abruptly stopping them, can avoid or minimize the potential adverse discontinuation effects associated with most psychotropic drugs.

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.

Posted Online: August 23, 2010

For nurses in clinical practice, understanding the pharmacology of drugs their patients take is relevant to understanding their therapeutic uses, side effect profiles, and adverse discontinuation effects. In this series of four articles, I have reviewed the potential adverse effects associated with the discontinuation of various psychotropic drugs. This final article covers benzodiazepine, glutamate, opioid, and stimulant drugs.

Benzodiazepine and Sedative-Hypnotic Drugs

The amino acid gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). GABA receptor systems are the target of a wide range of drugs active on the CNS, including anti-anxiety, sedative-hypnotic, general anesthetic, and anticonvulsant drugs.

The main GABA receptor complexes are referred to as GABA-A, GABA-B, and GABA-C. The GABA-A receptor complex is the most clinically important, and it is composed of at least five subunits. Benzodiazepine receptor agonist drugs (BzRAs) work by binding to GABA-A receptors in the brain. The two BzRA drug classes are referred to as benzodiazepine and non-benzodiazepine drugs. The benzodiazepine drugs bind non-specifically to the GABA-A receptor complex and are related by their similar central chemical structure, but they have different chemical side chains that result in important pharmacokinetic differences (influencing their elimination half-lives and whether they have active or inactive metabolites). Drugs that have long elimination half-lives and active metabolites will accumulate in the body with chronic use and are therefore more prone to adverse effects. This is especially true for older adults and for those patients with impaired liver or kidney function (who will have greater problems metabolizing or clearing medications). For this reason, though, abruptly stopping benzodiazepine drugs with slower or delayed elimination is not likely to precipitate any noticeable withdrawal effects.

Eight benzodiazepine drugs are approved for the treatment of anxiety but are also commonly used for insomnia: alprazolam (Xanax®), chlordiazepoxide (Librium®), clonazepam (Klonopin®), clorazepate (Tranxene®), diazepam (Valium®), halazepam (Paxipam®), lorazepam (Ativan®), and oxazepam (Serax®). These benzodiazepine drugs bind nonspecifically to the GABA-A complex. They have hypnotic, anti-anxiety, and anticonvulsant effects, and tolerance may develop with chronic use. Abrupt discontinuation can lead to increased anxiety, agitation, sleep disturbances, delirium, and seizures (MacKinnon & Parker, 1982; Rickels, Schweizer, Case, & Greenblatt, 1990). However, this is more likely to occur with the drugs having short elimination half-lives and no active metabolites (i.e., alprazolam, lorazepam, and oxazepam). Because GABA has a modulating effect on dopamine function in the brain, some benzodiazepine drugs are used for the treatment of antipsychotic drug-induced akathisia (e.g., lorazepam), catatonia (e.g., lorazepam), and restless legs syndrome (e.g., clonazepam). On the basis of this dopamine-modulating effect, abrupt discontinuation of benzodiazepine drugs has been rarely associated with the development of catatonia and neuroleptic malignant syndrome (Bobolakis, 2000; Brown & Freeman, 2009; Deuschle & Lederbogen, 2001; Rosebush & Mazurek, 1996).

Five other benzodiazepine drugs are approved specifically for the short-term treatment of insomnia: estazolam (ProSom®), flurazepam (Dalmane®), quazepam (Doral®), temazepam (Restoril®), and triazolam (Halcion®). Similar to all benzodiazepine drugs, they bind nonspecifically to the GABA-A complex and have hypnotic, anti-anxiety, and anticonvulsant properties, but they are usually not used for treating anxiety. Tolerance may develop with chronic use, and abrupt discontinuation can lead to increased anxiety, agitation, sleep disturbances, delirium, and seizures. They have a rapid onset of effect for initiating sleep, but they differ in their elimination half-lives, and some have active metabolites. The drugs with short to intermediate half-lives (i.e., triazolam, temazepam, and estazolam) may be more prone to abrupt discontinuation effects after prolonged use. Patients taking those drugs with longer half-lives (i.e., quazepam and flurazepam) and those with active metabolites (i.e., estazolam, quazepam, and flurazepam) may be less likely to experience acute discontinuation effects after chronic use.

Three non-benzodiazepine BzRA drugs are approved for insomnia: zolpidem (Ambien®, Ambien CR®, Edluar® sublingual tablets, Zolpimist® oral spray), zaleplon (Sonata®), and eszopiclone (Lunesta®). They have a rapid onset of effect for initiating sleep. These drugs are chemically unrelated to the benzodiazepines. They bind more selectively to specific subunits on the GABA-A receptor complex. This may explain why they have hypnotic effects without significant anti-anxiety or anticonvulsant effects. This subunit selectivity may also explain the relatively better tolerability and lower risk for abuse of non-benzodiazepines compared with benzodiazepines. Abrupt discontinuation after long-term use may lead to rebound insomnia but is not likely to be associated with seizures or other serious withdrawal effects.

Melatonin, a hormone synthesized from the 5HT receptor and secreted by the pineal gland, regulates sleep-wake cycles. It is effective for circadian rhythm sleep disturbances (e.g., associated with jet lag), but it is only modestly effective in the treatment of insomnia unrelated to circadian rhythm sleep disturbances. Ramelteon (Rozerem®) is a synthetic analog of melatonin. It is a melatonin MT1 and MT2 receptor agonist drug currently approved for the treatment of insomnia characterized by difficulty falling asleep. It is structurally unrelated to BzRA drugs and does not bind to any GABA receptor. Other than rebound insomnia, serious withdrawal effects have not been associated with discontinuation.

Glutamate-Modulating Drugs

In contrast to the inhibitory amino acid GABA, glutamate is the major excitatory amino acid neurotransmitter throughout the CNS. Glutamate receptor systems are very complex, and they can be segregated into various distinct receptor subtypes according to their molecular and pharmacological properties. One important type of glutamate receptor is the N-methyl-D-aspartate (NMDA) receptor, which also has multiple subtypes.

Memantine (Namenda®), used for the treatment of Alzheimer’s disease, is a weakly binding NMDA receptor antagonist. It does not affect GABA or other neurotransmitter receptors. Abrupt discontinuation is not associated with serious adverse effects.

Acamprosate (Campral®), used for the maintenance of abstinence in alcohol abuse, has a chemical structure similar to the amino acids taurine and GABA and attenuates the effects of glutamate. It is not associated with the development of tolerance during long-term use and has not been associated with abrupt discontinuation effects.

Opioid Receptor Drugs

Opioid receptor agonist drugs are used as analgesics for the treatment of various pain conditions. Tolerance commonly occurs with chronic use, and abruptly stopping them will quickly precipitate a withdrawal syndrome characterized by anxiety, runny nose, dilated pupils, elevated heart rate, increased blood pressure, sweating, nausea, abdominal pain, and diarrhea. Multiple organ systems are involved in the withdrawal syndrome because opioid receptors are widely distributed throughout the CNS and peripheral nervous system (PNS), and they modulate the activity of other neurotransmitters.

Methadone (Dolophine®), a synthetic opioid analgesic drug, is an opioid receptor agonist used for analgesia, detoxification from opioid drug addictions, and as a maintenance treatment for opioid dependence. Abrupt discontinuation is associated with opioid withdrawal syndrome.

Buprenorphine (Buprenex®, Subutex®), a synthetic opioid analgesic drug, is a mixed opioid receptor agonist/antagonist used for analgesia, detoxification from opioid drug addictions, and as a treatment for opioid dependence. Although the mixed agonist/antagonist receptor effect may mitigate the develop of tolerance, abrupt discontinuation can still lead to an opioid withdrawal syndrome.

Naltrexone (ReVia®) is a pure opioid receptor antagonist drug used for rapid detoxification from opioid drug addictions and for the treatment of opioid dependence and alcohol dependence. Discontinuation is not likely to be associated with an opioid withdrawal syndrome.

Buprenorphine/naloxone (Suboxone®) is a combination product used for the maintenance treatment of opioid dependence. Because naloxone (Narcan®) is a pure opioid receptor antagonist, discontinuation of the buprenorphine/naloxone combination product after chronic use is not associated with opioid withdrawal syndrome.

Stimulant Drugs

The two main stimulant drug classes are methylphenidate compounds (Ritalin® and others) and amphetamine compounds (Adderall® and others). Drugs in both classes are available in many different formulations. Stimulant drugs facilitate the presynaptic release and block the presynaptic reuptake of the neurotransmitters norepinephrine and dopamine. They may act as direct agonists on alpha-adrenergic and beta-adrenergic receptors in the CNS. Formulations of methylphenidate and amphetamine are approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) and narcolepsy, and they are used for daytime somnolence in patients with sleep apnea. They may act as direct agonists on alpha-adrenergic and beta-adrenergic receptors in the CNS and PNS. In the CNS, they may activate the brainstem reticular activating system and other arousal systems throughout the brain. In the PNS, increased heart rate and blood pressure, mydriasis, bronchodilation, and contraction of the urinary sphincter suggest that they activate the sympathetic autonomic nervous system.

When stimulant drugs are used for treating ADHD, abrupt discontinuation will usually result in an immediate and prominent return of cognitive symptoms (e.g., attention, concentration) and behavioral symptoms (e.g., hyperactivity). With chronic stimulant use, physiological tolerance will develop. As a result, discontinuation is associated with depression, lethargy, apathy, impaired cognition, increased appetite, and weight gain (Lago & Kosten, 1994). Motor tics and dyskinesia have been associated with the use of stimulant drugs. When stimulant drugs are used in combination with antipsychotic drugs (i.e., for treating severe behavioral dyscontrol in individuals with ADHD), abruptly stopping the stimulant drug has been associated with acute dystonic reactions (McLaren, Cauble, & Barnett, 2010).

Modafinil (Provigil®) and armodafinil (Nuvigil®) are CNS stimulant drugs unrelated to methylphenidate or amphetamine. They are both approved for the treatment of narcolepsy and excessive daytime sleepiness associated with sleep apnea, and they are sometimes used as an alternative treatment for ADHD. The mechanism of action of these drugs is uncertain, but they may activate alpha-adrenergic and dopamine activity in the brain. Unlike methylphenidate or amphetamine, they do not have PNS effects and are not prone to the development of tolerance. Abrupt withdrawal effects are unlikely, although apathy and lethargy are possible.

Conclusion

Serious adverse effects are likely to occur only after abrupt discontinuation of benzodiazepine drugs, and they should almost always be tapered. Prominent discontinuation effects are seen with opioid and stimulant drugs, but these are usually not serious. Tapering medication, rather than abruptly stopping them, can avoid or minimize the potential adverse discontinuation effects associated with most psychotropic drugs. Nurses should be familiar with the range of discontinuation effects associated with all types of psychotropic drugs. This knowledge will be relevant to nurses who monitor patients during pharmacotherapy and for nurses who provide counseling and education to patients and families about medication adherence and what to expect if medications are stopped for any reason.

References

  • Bobolakis, I. (2000). Neuroleptic malignant syndrome after antipsychotic drug administration during benzodiazepine withdrawal. Journal of Clinical Psychopharmacology, 20, 281–283. doi:10.1097/00004714-200004000-00033 [CrossRef]
  • Brown, M. & Freeman, S. (2009). Clonazepam withdrawal-induced catatonia. Psychosomatics, 50, 289–292. doi:10.1176/appi.psy.50.3.289 [CrossRef]
  • Deuschle, M. & Lederbogen, F. (2001). Benzodiazepine withdrawal-induced catatonia. Pharmacopsychiatry, 34, 41–42. doi:10.1055/s-2001-15188 [CrossRef]
  • Lago, J.A. & Kosten, T.R. (1994). Stimulant withdrawal. Addiction, 89, 1477–1481. doi:10.1111/j.1360-0443.1994.tb03746.x [CrossRef]
  • MacKinnon, G.L. & Parker, W.A. (1982). Benzodiazepine withdrawal syndrome: A literature review and evaluation. American Journal of Drug and Alcohol Abuse, 9, 19–33. doi:10.3109/00952998209002608 [CrossRef]
  • McLaren, J.L., Cauble, S. & Barnett, R.J. (2010). Aripiprazole induced acute dystonia after discontinuation of a stimulant medication. Journal of Clinical Psychopharmacology, 30, 77–78. doi:10.1097/JCP.0b013e3181c92eb2 [CrossRef]
  • Rickels, K., Schweizer, E., Case, W.G. & Greenblatt, D.J. (1990). Long-term therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation. Archives of General Psychiatry, 47, 899–907.
  • Rosebush, P.I. & Mazurek, M.F. (1996). Catatonia after benzodiazepine withdrawal. Journal of Clinical Psychopharmacology, 16, 315–319. doi:10.1097/00004714-199608000-00007 [CrossRef]
Authors

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: .HowlandRH@upmc.edu

10.3928/02793695-20100730-04

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