Zolpidem dependence with delayed-onset opioid-like withdrawal symptoms

Dear Editor, In Taiwan, zolpidem is widely used for insomnia due to its favorable side effect profile and lower potential for dependence. However, there have been reports of zolpidem dependence and withdrawal effects. Herein, we present a case of zolpidem dependence that resulted in opioid-like withdrawal symptoms. CASE REPORT Mrs. A, a 46-year-old housewife, presented with chronic sleep disturbances. She had no history of substance dependence but had used over-the-counter analgesics for chronic headaches, without an opioid component. Over the past decade, she intermittently sought psychiatric care for insomnia and occasionally used hypnotics. Two years prior, Mrs. A began treatment with zolpidem at a dose of 10 mg/day. Over the following 6 months, she progressively increased the dosage and frequency of zolpidem use, reaching 350–400 mg/day for over a year. She found that zolpidem's euphoric and stimulating effects helped her manage stress, leading to its daytime usage. Gradually, Mrs. A became unable to discontinue zolpidem without experiencing general malaise and resorted to extensive efforts, including illicit means, to procure the drug. Despite awareness of the risks, she continued high-dose usage, which led to memory impairment, reduced complex task performance, and emotional instability. Mrs. A meets at least six DSM-5 Criterion A criteria for sedative, hypnotic, or anxiolytic use disorder. After realizing the inappropriate behavioral pattern, she abruptly discontinued zolpidem. She initially felt well, but 4 days later, she experienced marked anxiety, yawning, rhinorrhea, lacrimation, tremors, restlessness, kicking movements, and strong cravings. Mrs. A sought help at a hospital's emergency room where diazepam was administered. However, the symptoms recurred hours later, prompting her to seek further management at our outpatient department. To prevent further withdrawal symptoms, she was prescribed venlafaxine and clonazepam, enabling successful zolpidem tapering. DISCUSSION Although zolpidem is pharmacologically assumed to have lower potential for abuse than benzodiazepines, some patients take zolpidem as self-medication to manage their stresses, eventually leading to dependence due to its anxiolytic and stimulating effects.1 Zolpidem withdrawal symptoms include agitation, anxiety, panic attacks, tremors, nausea, and vomiting. Rarely, it may cause hallucinations, delirium, and epilepsy. In our patient, opioid-like withdrawal symptoms emerged after discontinuing high-dose zolpidem. Similar symptoms were documented in cases of intravenous zolpidem dependence.2 Another case report described a man with a previous history of heroin use developed zolpidem dependence at a dose of 400 mg/day. Upon cessation, he quickly exhibited classic opioid withdrawal symptoms.3 To our knowledge, this is the first reported case of oral zolpidem dependence resulting in opioid-like withdrawal symptoms in a patient with no prior opioid use. The analgesic effects of zolpidem and opioids have been extensively examined. One systematic review revealed that coadministering 5–10 mg zolpidem with other analgesics significantly reduces pain intensity.4 Another study demonstrates the antinociceptive effect of zolpidem through the mediation of both adrenoreceptor and opioid mechanism in mice.5 Zolpidem exhibits a dose-dependent antinociceptive effect when administered subcutaneously. This case report reminds clinicians that zolpidem dependence can occur and may present with opioid-like withdrawal symptoms following prolonged use of high doses. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names 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 Nil. Conflicts of interest There are no conflicts of interest.