Barbiturates and benzodiazepines (BZDs) can relieve insomnia and high levels of anxiety. Effects of barbiturates are similar to that of alcohol. Barbiturate use entails risk of addiction, and death from accidental or suicidal overdose. In the 1970s, the safer BZDs became available. Like barbiturates, BZDs facilitate the neural inhibitory action of the neurotransmitter GABA, but are unlikely to produce pleasurable intoxication and are less addictive than barbiturates. BZDs can impair driving and increase the probability of accidental falls, especially when used concurrently with alcohol. Stopping extended intake of BZDs can result in a withdrawal syndrome of anxiety, insomnia, and a general feeling of malaise. Addiction to BZDs occurs most often in individuals with an SUD of another addictive drug. As a secondary drug of abuse, BZDs can potentiate the effects of opioid drugs or alcohol, and relieve the anxiety and agitation of addictive stimulant use. Newer drugs including zolpidem (Ambien), benzodiazepine-receptor agonists with little abuse potential that produce a brief hypnotic effect with little residual sedation the following day, are now most often used to treat insomnia.

Opioid drugs suppress pain and relieve emotional distress. IV injection can produce intense pleasure. Oxycodone, heroin, and other opioids mimic the actions of endogenous opioids that modulate pain and stimulate pleasurable sensations. A painful withdrawal syndrome consists of intense anxiety, irritability, vomiting, diarrhea, and muscle pain. Stimuli related to opioid use elicit withdrawal symptoms long after drug use has stopped. A 21st-century upsurge in medical use and recreational misuse preceded a four-fold increase in fatal opioid overdoses. Many use opioids for mood improvement after treatment for temporary pain. About 1/7 of these misusers develop an opioid SUD. Risk factors include use of other addictive drugs, and a stressful lifestyle. Of the 5 percent of misusers who use heroin and fentanyl, 2/3 become addicted to these illicit opioids. Most chronic-pain patients, receiving long-term opioid treatment, do not become addicted, although they can experience withdrawal symptoms. Opioids improve functioning for these drug-dependent individuals, as opposed to impairment of function for addicts. Opioid addiction can be managed by use of the replacement drugs methadone and bupropion.