What are opioids?
Opioids are medications that act on opioid receptors in both the spinal cord and brain to reduce the intensity of pain-signal perception. They also affect brain areas that control emotion, which can further diminish the effects of painful stimuli. They have been used for centuries to treat pain, cough, and diarrhea.28 The most common modern use of opioids is to treat acute pain. However, since the 1990s, they have been increasingly used to treat chronic pain, despite sparse evidence for their effectiveness when used long term.29 Indeed, some patients experience a worsening of their pain or increased sensitivity to pain as a result of treatment with opioids, a phenomenon known as hyperalgesia.30
Importantly, in addition to relieving pain, opioids also activate reward regions in the brain causing the euphoria—or high—that underlies the potential for misuse and substance use disorder. Chemically, these medications are very similar to heroin, which was originally synthesized from morphine as a pharmaceutical in the late 19th century.31 These properties confer an increased risk of substance use disorder even in patients who take their medication as prescribed.29
Overdose is another significant danger with opioids, because these compounds also interact with parts of the brain stem that control breathing. Taking too much of an opioid can suppress breathing enough that the user suffocates. An overdose can be reversed (and fatality prevented) if the compound naloxone is administered quickly (see "Reversing an Opioid Overdose with Naloxone").
Prescription opioid medications include hydrocodone, oxycodone, oxymorphone, morphine, codeine, fentanyl, and others. Hydrocodone products are the most commonly prescribed in the United States for a variety of indications, including dental- and injury-related pain.32 Oxycodone and oxymorphone are also prescribed for moderate to severe pain relief.33,34 Morphine is often used before and after surgical procedures to alleviate severe pain, and codeine is typically prescribed for milder pain.28 In addition to their pain-relieving properties, some of these drugs—codeine and diphenoxylate, for example—are used to relieve coughs and severe diarrhea.28
How do opioids affect the brain and body?
Opioids act by attaching to and activating opioid receptor proteins, which are found on nerve cells in the brain, spinal cord, gastrointestinal tract, and other organs in the body.28 When these drugs attach to their receptors, they inhibit the transmission of pain signals. Opioids can also produce drowsiness, mental confusion, nausea, constipation, and respiratory depression, and since these drugs also act on brain regions involved in reward, they can induce euphoria, particularly when they are taken at a higher-than-prescribed dose or administered in other ways than intended. For example, OxyContin® is an oral medication used to treat moderate to severe pain through a slow, steady release of the opioid. Some people who misuse OxyContin® intensify their experience by snorting or injecting it.This is a very dangerous practice, greatly increasing the person’s risk for serious medical complications, including overdose
Understanding Dependence, Addiction, and Tolerance
Dependence occurs as a result of physiological adaptations to chronic exposure to a drug. It is often a part of addiction, but they are not equivalent. Addiction involves other changes to brain circuitry and is distinguished by compulsive drug seeking and use despite negative consequences.36
Those who are dependent on a medication will experience unpleasant physical withdrawal symptoms when they abruptly reduce or stop use of the drug. These symptoms can be mild to severe (depending on the drug) and can usually be managed medically or avoided by slowly tapering down the drug dosage.37
Tolerance, or the need to take higher doses of a medication to get the same effect, often accompanies dependence. When tolerance occurs, it can be difficult for a physician to evaluate whether a patient is developing a drug problem or has a medical need for higher doses to control his or her symptoms. For this reason, physicians should be vigilant and attentive to their patients’ symptoms and level of functioning and should screen for substance misuse when tolerance or dependence is present.29
What are the possible consequences of prescription opioid misuse?
When taken as prescribed, patients can often use opioids to manage pain safely and effectively. However, it is possible to develop a substance use disorder when taking opioid medications as prescribed. This risk and the risk for overdose increase when these medications are misused. Even a single large dose of an opioid can cause severe respiratory depression (slowing or stopping of breathing), which can be fatal; taking opioids with alcohol or sedatives increases this risk.4,26
When properly managed, short-term medical use of opioid pain relievers—taken for a few days following oral surgery, for instance—rarely leads to an opioid use disorder or addiction. But regular (e.g., several times a day, for several weeks or more) or longer-term use of opioids can lead to dependence (physical discomfort when not taking the drug), tolerance (diminished effect from the original dose, leading to increasing the amount taken), and, in some cases, addiction (compulsive drug seeking and use) (see "Understanding Dependence, Addiction, and Tolerance"). With both dependence and addiction, withdrawal symptoms may occur if drug use is suddenly reduced or stopped. These symptoms may include restlessness, muscle and bone pain, insomnia, diarrhea, vomiting, cold flashes with goose bumps, and involuntary leg movements.31
Misuse of prescription opioids is also a risk factor for transitioning to heroin use. Read more about the relationship between prescription opioids and heroin in NIDA's Prescription Opioids and Heroin Research Report.
How is prescription opioid misuse related to chronic pain?
Health care providers have long wrestled with how best to treat the more than 100 million Americans who suffer from chronic pain.38 Opioids have been the most common treatment for chronic pain since the late 1990s, but recent research has cast doubt both on their safety and their efficacy in the treatment of chronic pain when it is not related to cancer or palliative care.29 The potential risks involved with long-term opioid treatment, such as the development of drug tolerance, hyperalgesia, and addiction, present doctors with a dilemma, as there is limited research on alternative treatments for chronic pain. Patients themselves may even be reluctant to take an opioid medication prescribed to them for fear of becoming addicted.
Estimates of the rate of opioid misuse among chronic pain patients vary widely as a result of differences in treatment duration, insufficient research on long-term outcomes, disparate study populations, and different outcome measures (e.g., dependence versus OUD or addiction). One study assessing current criteria for OUD in a large number of chronic pain patients receiving opioids found that 28.1 percent had mild OUD, 9.7 percent had moderate OUD, and 3.5 percent had severe OUD (addiction).39
To mitigate addiction risk, physicians should adhere to the CDC Guideline for Prescribing Opioids for Chronic Pain. Before prescribing, physicians should assess pain and functioning, consider if non-opioid treatment options are appropriate, discuss a treatment plan with the patient, evaluate the patient’s risk of harm or misuse, and co-prescribe naloxone to mitigate the risk for overdose (see NIDA's webpage on naloxone). When first prescribing opioids, physicians should give the lowest effective dose for the shortest therapeutic duration. As treatment continues, the patient should be monitored at regular intervals, and opioid treatment should be continued only if meaningful clinical improvements in pain and functioning are seen without harm.29
- CNS Depressants
What are CNS depressants?
CNS depressants, a category that includes tranquilizers, sedatives, and hypnotics, are substances that can slow brain activity. This property makes them useful for treating anxiety and sleep disorders. The following are among the medications commonly prescribed for these purposes40:
- Benzodiazepines, such as diazepam, clonazepam, and alprazolam, are sometimes prescribed to treat anxiety, acute stress reactions, and panic attacks. Clonazepam may also be prescribed to treat seizure disorders and insomnia. The more sedating benzodiazepines, such as triazolam and estazolam are prescribed for short-term treatment of sleep disorders. Usually, benzodiazepines are not prescribed for long-term use because of the high risk for developing tolerance, dependence, or addiction.
- Non-benzodiazepine sleep medications, such as zolpidem, eszopiclone, and zaleplon, known as z-drugs, have a different chemical structure but act on the same GABA type A receptors in the brain as benzodiazepines. They are thought to have fewer side effects and less risk of dependence than benzodiazepines.
- Barbiturates, such as mephobarbital, phenobarbital, and pentobarbital sodium, are used less frequently to reduce anxiety or to help with sleep problems because of their higher risk of overdose compared to benzodiazepines. However, they are still used in surgical procedures and to treat seizure disorders.
How do CNS depressants affect the brain and body?
Most CNS depressants act on the brain by increasing activity at receptors for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Although the different classes of CNS depressants work in unique ways, it is through their ability to increase GABA signaling—thereby increasing inhibition of brain activity—that they produce a drowsy or calming effect that is medically beneficial to those suffering from anxiety or sleep disorders.40
What are the possible consequences of CNS depressant misuse?
Despite their beneficial therapeutic effects, benzodiazepines and barbiturates have the potential for misuse and should be used only as prescribed.40 The use of non-benzodiazepine sleep aids, or z-drugs, is less well-studied, but certain indicators have raised concern about their misuse potential as well.41
During the first few days of taking a depressant, a person usually feels sleepy and uncoordinated, but as the body becomes accustomed to the effects of the drug and tolerance develops, these side effects begin to disappear. If one uses these drugs long term, he or she may need larger doses to achieve the therapeutic effects. Continued use can also lead to dependence and withdrawal when use is abruptly reduced or stopped (see "Understanding Dependence, Addiction, and Tolerance"). Because CNS depressants work by slowing the brain’s activity, when an individual stops taking them, there can be a rebound effect, resulting in seizures or other harmful consequences.40
Although withdrawal from benzodiazepines can be problematic, it is rarely life threatening, whereas withdrawal from prolonged use of barbiturates can have life-threatening complications.42 Therefore, someone who is thinking about discontinuing a CNS depressant or who is suffering withdrawal after discontinuing use should speak with a physician or seek immediate medical treatment.
What are stimulants?
Stimulants increase alertness, attention, and energy, as well as elevate blood pressure, heart rate, and respiration. Historically, stimulants were used to treat asthma and other respiratory problems, obesity, neurological disorders, and a variety of other ailments. But as their potential for misuse and addiction became apparent, the number of conditions treated with stimulants has decreased.43 Now, stimulants are prescribed for the treatment of only a few health conditions, including attention-deficit hyperactivity disorder (ADHD), narcolepsy, and occasionally treatment-resistant depression.44–46
How do stimulants affect the brain and body?
Stimulants, such as dextroamphetamine and methylphenidate, act in the brain on the family of monoamine neurotransmitter systems, which include norepinephrine and dopamine. Stimulants enhance the effects of these chemicals. An increase in dopamine signaling from nonmedical use of stimulants can induce a feeling of euphoria, and these medications’ effects on norepinephrine increase blood pressure and heart rate, constrict blood vessels, increase blood glucose, and open up breathing passages.47
What are the possible consequences of stimulant misuse?
As with other drugs in the stimulant category, such as cocaine, it is possible for people to become dependent on or addicted to prescription stimulants. Withdrawal symptoms associated with discontinuing stimulant use include fatigue, depression, and disturbed sleep patterns. Repeated misuse of some stimulants (sometimes within a short period) can lead to feelings of hostility or paranoia, or even psychosis.31 Further, taking high doses of a stimulant may result in dangerously high body temperature and an irregular heartbeat. There is also the potential for cardiovascular failure or seizures.47
The dramatic increases in stimulant prescriptions over the last 2 decades have led to their greater availability and to increased risk for diversion and nonmedical use.48 When taken to improve properly diagnosed conditions, these medications can greatly enhance a patient’s quality of life. However, because many perceive them to be generally safe and effective, prescription stimulants are being misused more frequently.
Stimulants increase wakefulness, motivation, and aspects of cognition, learning, and memory. Some people take these drugs in the absence of medical need in an effort to enhance mental performance.49 Militaries have long used stimulants to increase performance in the face of fatigue, and the United States Armed Forces allow for their use in limited operational settings.50 The practice is now reported by some professionals to increase their productivity, by older people to offset declining cognition, and by both high school and college students to improve their academic performance.
Nonmedical use of stimulants for cognitive enhancement poses potential health risks, including addiction, cardiovascular events, and psychosis. The use of pharmaceuticals for cognitive enhancement has also sparked debate over the ethical implications of the practice. Issues of fairness arise if those with access and willingness to take these drugs have a performance edge over others, and implicit coercion takes place if a culture of cognitive enhancement gives the impression that a person must take drugs in order to be competitive.49,51
Future Research Directions
There are a handful of psychedelic drugs being researched and used for mental health treatments. These drugs carry a risk, and must be administered under medical supervision. Information on these human studies can be found on clinicaltrials.gov. These include:
- Ketamine, a dissociative drug, which has been approved by the FDA under the name esketamine for treatment resistant depression
- MDMA, a synthetic drug chemically similar to both stimulants and hallucinogens, which is being studied under an FDA breakthrough therapy designation for post-traumatic stress disorder
- Psilocybin, extracted from certain types of mushrooms, is being studied under a breakthrough therapy designation for treatment-resistant depression