There are several mechanisms behind tolerance, including changes in the metabolism of a drug, cellular changes, or behavioral effects. Tolerance is not always negative, and people may develop a tolerance to the side effects of a drug over time as well. It’s important to understand that tolerance is not the same as dependence or addiction, but in the case of substances of misuse, such as some painkillers and alcohol, tolerance can predispose a person to these problems.
What Is Drug Tolerance?
Tolerance is defined as the diminishing effect of a medication following repeated administration at a certain dose. It is often a normal adaptive response to ingested drugs, as the body tries to maintain homeostasis or balance. The development of tolerance with a specific drug can vary between different people (there is a genetic influence); with other drugs a person is taking; and with underlying medical conditions that are present. For example, with opioids, people may develop more tolerance to the euphoria caused by the drug than to the respiratory depression caused by the drug.
Acute vs. Chronic
Tolerance often develops chronically over many weeks but can occur rapidly as well. “Tachyphylaxis” is the term used to describe the very rapid onset of tolerance, such as that seen after a single dose with cocaine or LSD. Tachyphylaxis also often occurs with antidepressant medications.
Effects vs. Side Effects
As noted above, tolerance may be a negative finding, such as when a drug loses effectiveness over time, but can also be positive, such as when tolerance develops to side effects such as nausea or fatigue. In the case of allergy shots (desensitization), it’s the development of tolerance that’s responsible for the effectiveness of the treatment.
Tolerance vs. Resistance
Resistance also differs from tolerance. With resistance (such as to antibiotics or cancer drugs), resistance develops because bacteria or cancer cells make substances that lead to the drug not working.
Tolerance vs. Addiction vs. Dependence
The differences between tolerance, dependence, and addiction are important. Many drugs that cause tolerance do have addictive potential, but becoming tolerant does not mean a person is addicted to the drug. Similarly, dependence is defined as the occurrence of withdrawal symptoms when the drug is removed and may occur in the absence of tolerance or addiction.
Mechanisms
There are several different ways in which tolerance to a drug may develop:
Pharmacodynamic resistance: In pharmacodynamic, dispositional, or functional tolerance, changes at the cellular level leading to resistance. For example, binding of a drug to a particular receptor on the surface of cells (such as opioid receptors) may fail to cause the signals to be transmitted as in the past, or the body may produce fewer receptors on the surface of cells for the drug to bind with.Metabolic tolerance: With this mechanism of tolerance, a drug may be broken down and cleared from the body before it reaches its site of action. For example, alcohol can induce the activity of liver enzymes that metabolize the “drug.“Behavioral or learned tolerance: In learned tolerance, people may become accustomed to the effect of a drug. For example, some people who are long-term drinkers can better “hold” their alcohol, even with the same blood concentration.Conditioned tolerance: Environmental cues can also lead to tolerance. An example would be a person who routinely drinks at a bar having better eye-hand coordination at the bar than he or she would have at home (after the same number of drinks).
Examples of Medication Tolerance
Medication tolerance is most often (but not always) related to drugs that affect your body’s brain and nervous system. A few examples include:
Painkillers such as oxycodone Tranquilizers such as Valium (Diazepam) Over-the-counter sleep aids such as Benadryl (diphenhydramine)
Management and Treatment
How tolerance is managed depends on the particular drug, what it is being used for, and alternatives that are available. In some cases, increasing the dose may result in the drug working again (though it may also amplify tolerance at that dose). If a drug can be discontinued for some time, what’s known as a drug holiday, it can often be restarted without tolerance (though tolerance may again occur in time).
Tolerance and Cancer Treatment
In some settings, such as terminal cancer, apparent tolerance to opioid medications is more often due to worsening cancer (tumor growth or new metastases) rather than tolerance to the drugs. When apparent tolerance occurs, it’s extremely important to rule out other potential causes of increased pain. While there is cross-tolerance between different opioids, this is often not complete, and changing to another drug in this class may be helpful. Many of these drugs can also be given at very high doses (there doesn’t appear to be a ceiling or maximum dose), and, when increased gradually, there is less concern over problems such as respiratory depression.
Tolerance and Substances of Misuse
When a person first consumes a potential substance of misuse, be it alcohol, opioids or nicotine, the effects are more potent than they ever will be again. On repeated administration of this drug, a person needs larger and larger amounts to feel any desired effects thus setting up a vicious cycle of abuse, dependence, and withdrawal. The phenomenon of needing more drugs to produce the desired effect is called tolerance.
Cross-Over
When a person becomes tolerant of a certain central nervous system (CNS) depressant like alcohol, then this person usually becomes tolerant of other drugs of misuse like heroin. (Technically, opioids like heroin aren’t CNS depressants although they have depressant properties.) This phenomenon is called cross-tolerance.
Dangers
Tolerance can be particularly dangerous for several reasons. When tolerance develops to a different degree to different effects, the risk of overdose can be significant. This is a tragic problem with the opioid epidemic, as tolerance develops more quickly to the euphoric properties of these drugs than to the respiratory depressive properties. As noted, cross-over can vary, and people who switch off between drugs such as heroin, codeine, morphine, and others, may end up taking a higher “dose” than they had planned if there is less tolerance to the next drug. For those in recovery, tolerance can be dangerous in another way. Tolerance often decreases with time off of a drug. If a person who has been abstinent from the drug for a period of time resumes his previous level of use, a life-threatening overdose may occur. Finally, many abused substances are combined with other drugs for which physiological tolerance does not develop. For example, opioids may be combined with Tylenol (acetaminophen). While tolerance may develop to higher doses of the narcotic so that respiratory depression does not occur, an excess of Tylenol (even just a small excess) from products such as Vicodin (hydrocodone plus acetaminophen) could lead to liver failure.
Differences in Tolerance
Certain people exhibit a rapid acute tolerance or initial tolerance to a drug. These people may be at higher risk of drug dependence or substance misuse.
What to Do If You Are Concerned
If you feel that you may be experiencing tolerance to any substance of misuse, it’s extremely important to inform your physician and get help. Substance misuse and drug dependence can have terrible and deadly personal consequences for you, your loved ones and society as a whole. Please remember that there are health care professionals and support groups that specialize in drug treatment and are empathetic to your needs. If you or a loved one are struggling with substance use or addiction, contact the Substance Abuse and Mental Health Services Administration (SAMHSA) National Helpline at 1-800-662-4357 for information on support and treatment facilities in your area. For more mental health resources, see our National Helpline Database.
