|Ahead of print publication
Clinical challenges in managing zolpidem use disorder
K Ganesh Kini1, S Mohan Raju2
1 Department of Psychiatry, Yenepoya Medical College, Mangalore, Karnataka, India
2 Department of Psychiatry, Ramaiah Medical College, Bengaluru, Karnataka, India
|Date of Submission||09-Nov-2020|
|Date of Decision||06-Jan-2021|
|Date of Acceptance||13-Jan-2021|
|Date of Web Publication||11-Mar-2021|
K Ganesh Kini,
Department of Psychiatry, Yenepoya Medical College, University Road, Deralakatte, Mangalore - 575 018, Karnataka
Source of Support: None, Conflict of Interest: None
Zolpidem was popularized as a hypnotic with low abuse potential in the early years of its introduction. However, several cases of zolpidem use disorder necessitating medical intervention have been reported from across the world. The absence of their mention in standard treatment guidelines presents clinicians with significant challenges in managing craving and withdrawal symptoms in patients. We report a case of a 26-year-old male who presented to us with zolpidem misuse to cope with depression for two long years. We would like to draw attention to the clinical challenges we faced in managing the case. We urge apex health bodies to consider developing evidence-based recommendations or standards of treatment of zolpidem use disorder.
Keywords: Dependence, diazepam, hypnotic, misuse, zolpidem
| Introduction|| |
Zolpidem is an imidazopyridine with selective agonist action at the benzodiazepine-1 receptor. It is considered as a nonbenzodiazepine hypnotic as it lacks the diazepine ring. Yet, it acts at the benzodiazepine receptor and its actions can be blocked by the use of flumazenil which is an antagonist at the benzodiazepine receptor. Its use increased in the years following its introduction as it was marketed as a drug with low abuse potential unlike conventional hypnotics. However, in the years following the introduction of the drug, several studies indicated dependence potential including severe withdrawal reactions., Nevertheless, there are no standard guidelines for the management of zolpidem use disorder for clinicians. We would like to highlight the clinical challenges in the management of one such case of zolpidem misuse and the need for careful relook at the recommendations.
| Case Report|| |
Mr. X is a 26-year-old married male, working as a school lab assistant with no past or family history of mental illness who presented to us with a 2-year history of significant preoccupations with the death of a maternal cousin. He reported feelings of guilt and bitterness over his death. The patient subsequently developed pervasive depressed mood with frequent crying spells, lack of interest in previously pleasurable activities, social withdrawal, decreased sleep, and appetite along with significant weight loss. He also reported ideas of worthlessness, resulting in two unsuccessful deliberate self-harm attempts. The patient started self-medicating for sleep with zolpidem 10 mg tablets bought over the counter. He took 2–3 tablets per week for the first 1 year. He gradually increased it to everyday use. The patient was using 4–5 tablets per night at the time of consultation. He was reported to have used 8–10 tablets on a few occasions. He reported significant craving for the drug and also reported tremors and reduced sleep when he did not take it. The patient is reported to have shown sleepwalking thrice in the past 3 months; with episodes of wandering away in the middle of the night and engaging in grooming self. The last sleepwalking incident brought the substance taking behavior to family's attention who decided to bring him for psychiatric help. The patient was diagnosed with zolpidem use disorder with Major Depressive Disorder as per Diagnostic and Statistical Manual of Mental Disorders 5th Edition. He was offered inpatient care for 2 weeks and started on diazepam 30 mg, and doses were gradually tapered down and stopped over 4 months during outpatient follow-ups. No significant withdrawal symptoms were noted during the entire period. He was also started on tablet mirtazapine 30 mg in view of depression. He was simultaneously referred to the clinical psychologist for grief-related work. Psychotherapy sessions explored and highlighted patient's conflicts and more adaptive defenses were discussed. The patient responded favorably and maintained improvement for 4 months. However, he started to experience significant craving for the drug later and is reported to have relapsed. Subsequently, the patient was lost to follow-up.
| Discussion|| |
Zolpidem was promoted initially as a hypnotic with low abuse potential unlike conventional hypnotics such as the benzodiazepines. Zolpidem misuse, whenever reported, was attributed to the past history of substance use or secondary to other drugs of abuse. There has been increasing evidence that zolpidem too can cause dependence syndrome with significant potential for causing withdrawal seizures and withdrawal delirium. However, there are no clear guidelines on treating the dependence syndrome and associated withdrawal reactions even in the highly respected and widely used The Maudsley Prescribing Guidelines in Psychiatry. When we did a literature review to help us while treating the abovementioned patient, we were in a dilemma due to lack of substantial guidelines and general lack of consensus among clinicians on treatment for zolpidem use disorder. Various clinicians across the globe have tried a wide variety of drugs such as flumazenil infusion, Quetiapine, Oxazepam and Carbamazepine, Gabapentin, Pramipexole, and Mirtazapine to treat zolpidem use disorder.
Zolpidem acts selectively at benzodiazepine-1 receptor to increase affinity for gamma-aminobutyric acid (GABA) at the GABA receptor and hence proposed to have minimum dependence potential. However, at doses of 30–120 mg above the recommended dose, the selectivity at the benzodiazepine-1 receptor is lost, and it was noted that the tolerance-inducing potential of zolpidem was similar to that of benzodiazepines. We theorized that, as the patient was consuming zolpidem at substantially high doses, up to 80 mg on certain occasions, zolpidem must be acting as a nonselective agonist at benzodiazepine receptors. Hence, we made a decision to treat him with diazepam to prevent any withdrawal symptoms as it has a long half-life and hence less likely to produce severe withdrawal symptoms.
There is a genuine gap in existing guidelines for the management of zolpidem use disorder. We request apex health bodies such as the World Health Organization to commission development of high quality, evidence-based, user friendly clinical practice guidelines (CPG) for management of zolpidem use disorder for reducing variations in treatment practices while increasing safety. Focus should be not only on the development of CPG but also implementation, adaptation (to local milieu), and evolution (upon availability of new evidence).
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that their name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Soyka M, Bottlender R, Möller HJ. Epidemiological evidence for a low abuse potential of zolpidem. Pharmacopsychiatry 2000;33:138-41.
Haji Seyed Javadi SA, Hajiali F, Nassiri-Asl M. Zolpidem dependency and withdrawal seizure: A case report study. Iran Red Crescent Med J 2014;16:e19926.
Mattoo SK, Gaur N, Das PP. Zolpidem withdrawal delirium. Indian J Pharmacol 2011;43:729-30.
] [Full text]
Quaglio G, Lugoboni F, Fornasiero A, Lechi A, Gerra G, Mezzelani P. Dependence on zolpidem: Two case reports of detoxification with flumazenil infusion. Int Clin Psychopharmacol 2005;20:285-7.
Mariani JJ, Levin FR. Quetiapine treatment of zolpidem dependence. Am J Addict 2007;16:426.
Krueger TH, Kropp S, Huber TJ. High-dose zolpidem dependence in a patient with chronic facial pain. Ann Pharmacother 2005;39:773-4.
Fernandes WH, Pereira Yda S, O' Tereza S. A case of Zolpidem dependence successfully detoxified with gabapentin. Indian J Psychiatry 2013;55:290-2.
] [Full text]
Kandre D, Banwari G, Sharma P. Comorbid functional shoulder pain and zolpidem dependence treated with pramipexole. Indian J Psychol Med 2015;37:443-5.
] [Full text]
Bhatia MS, Kohli GS. Iatrogenic zolpidem dependence. J Neuropsychiatry Clin Neurosci 2014;26:E38.
Petroski RE, Pomeroy JE, Das R, Bowman H, Yang W, Chen AP, et al
. Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors. J Pharmacol Exp Ther 2006;317:369-77.