Which drug classes are associated with higher risk of rebound insomnia and withdrawal when discontinued?

• A. Orexin receptor antagonists.
• B. Antihistamines.
• C. Benzodiazepines and Z-drugs.
• D. Melatonin.

Answer: (C)

Rebound insomnia and withdrawal are most likely with drugs that produce physical dependence through adaptive changes in the brain with regular use. Benzodiazepines and Z-drugs fit this pattern because they enhance GABAergic inhibition at the GABA-A receptor, leading to sleep with continued use but also tolerance and dependence over time. When these medications are stopped abruptly, the brain struggles to regain normal sleep regulation, so insomnia tends to return and can be worse than baseline for a period. Withdrawal symptoms can also appear, such as anxiety, irritability, restlessness, tremors, sweating, and sometimes autonomic symptoms, reflecting this dependence.

Other sleep aids like antihistamines and melatonin generally have minimal or no meaningful withdrawal risks, and while orexin receptor antagonists can cause some residual sleep issues, they are not as strongly linked to rebound insomnia and withdrawal as benzodiazepines and Z-drugs.