Tolerance, physical dependence and addiction:
Definitions, clinical relevance and misconceptions

Health care professionals, patients and families have exaggerated concerns about opioids and their potential side effects, in particular tolerance, physical dependence and addiction. Therefore it is critically important to understand the meaning of these terms and their clinical relevance to the management of cancer pain.


Tolerance is a physiological state characterized by a decrease in the effects of a drug (e.g., analgesia, nausea or sedation) with chronic administration.

Clinical relevance:
It is important to distinguish between tolerance to analgesia and tolerance to side effects.

(1) Tolerance to analgesia.
Patients with unchanging pain can have a consistent level of pain relief from the same dose of opioids over time.[1-3] The need for higher doses of opioids is typically due to worsening pain and disease progression, rather than tolerance. If analgesic tolerance does develop, increase the dose until side effects are not tolerated.

(2) Tolerance to opioid side effects.
Tolerance usually develops to many of the side effects of opioids (sedation, nausea, itch) in a few days. Tolerance almost never develops to constipation. Constipation should always be anticipated and treated. If a patient does not tolerate the side effects of one opioid, another opioid should be tried.


  • To some, the need to increase the dose in response to the patient's report of pain is misinterpreted as a sign that tolerance may be developing. Unfortunately, this sometimes leads the physician to reduce the dose in a mistaken attempt to avoid or delay the development of tolerance. The appropriate response is to reassess the pain and increase the dose as indicated to relieve pain.
  • Sometimes, to prevent the development of analgesic tolerance, opioids are administered at intervals which are too far apart to maintain continuous pain relief. This practice is inappropriate because it subjects patients to needless cycles of pain and pain relief.
  • Often, health care professionals and patients are concerned about using opioids from the 3rd step of the WHO ladder, such as morphine, because of the mistaken belief that the medication will lose its analgesic effect; they want to save it until the pain is really severe.[4] This concern about analgesic tolerance is unfounded and can lead to inadequate pain management.
  • Some health care workers and patients believe that using morphine for pain relief will suppress respiration and possibly cause death. In fact, clinically significant respiratory depression and sedation are very rare in cancer patients. This is because tolerance to the sedative effects of morphine develop rapidly, and because pain reverses morphine's depressant effects.[5]


Physical dependence is the physiological adaptation of the body to the presence of an opioid. It is defined by the development of withdrawal symptoms when opioids are discontinued, when the dose is reduced abruptly or when an antagonist (e.g., naloxone) or an agonist-antagonist (e.g., pentazocine) is administered.[6]

Clinical relevance
Physical dependence is a normal and expected response to continuous opioid therapy. Physical dependence may occur within a few days of dosing with opioids, although it varies among patients. Physical dependence (indicated by withdrawal symptoms) does not mean that the patient is addicted.[6]

Health care workers should advise patients to take their pain medication as directed, and that withdrawal symptoms may occur if they reduce their dose or stop taking the medication.[7] Symptoms of withdrawal may include agitation, insomnia, diarrhea, sweating, and rapid heart beat. If the source of pain is successfully treated or removed, physical dependence is easily treated by gradually decreasing the opioid dose, e.g., reducing the daily dose by 10 to 25 percent every 2 days. When a daily dose of 10-15 mg of parenteral morphine (or its equivalent) is reached, maintain that dose for 2 days, then discontinue.

The development of physical dependence should not limit analgesic therapy. Antagonists and agonist-antagonists in the patient who is physically dependent should be strictly avoided because their use will neutralize the analgesic effect and cause a withdrawal syndrome.


  • Physical dependence is frequently equated mistakenly with addiction. It is incorrect to use the term 'physical dependence' (a physiological state) to describe addiction (a dysfunctional psychological and behavioral syndrome).[1]
  • Patients who express concern about physical dependence should be given correct information and reassured. Example: "Do not to stop taking your medication abruptly or you will have symptoms of withdrawal. If you no longer need opioids for pain relief (for example after a course of radiotherapy), your physician can gradually decrease your dose over several days."


While tolerance and physical dependence are physical changes in the body, addiction is defined by aberrant changes in behavior. Addiction is compulsive use of drugs for nonmedical reasons; it is characterized by a craving for mood altering drug effects, not pain relief.[8] Addiction means dysfunctional behavior, in sharp contrast to the improved function and quality of life that result from pain relief. Aberrant behaviors which indicate addiction may include: denial of drug use; lying; forgery of prescriptions; theft of drugs from other patients or family members; selling and buying drugs on the street; using prescribed drugs to get "high."[8]

Clinical relevance:
Addiction is extremely rare in cancer patients who use opioids for pain (see abstracts). Biochemical, social and psychological factors are more important in the development of addiction. Opioids should not be withheld for fear that a patient will become addicted. If a pain patient requests a strong analgesic, it is likely that the patient has inadequate pain control.


  • People who fear addiction, yet desire pain relief sometimes think "So what if I get addicted, I am going to die anyway." Such thinking creates an unnecessary trade-off between addiction and pain relief; in fact, addiction is rare and should not be a worry when opioids are used appropriately to relieve pain.
  • Patients and family members who express concern about addiction should be given correct information and reassured. Example: "Sometimes patients taking opioids for pain relief are concerned about addiction. However, you are taking opioids for pain relief whereas addicts take drugs to get high. You are not an addict if you take pain medications to relieve your pain."


Pseudo-addiction describes what happens when healthcare workers perceive as addictive behavior a pain patient's requests for more or stronger pain medications. In fact, the patient's behavior may be a response to inadequate pain management.[9] Pseudo-addictive behavior is pain-relief seeking behavior. Pseudo-addiction is an iatrogenic phenomenon, e.g. it is when problems result from the treatment efforts of health professionals.

Clinical relevance
Pseudo-addictive behavior may occur when analgesics are prescribed in inadequate doses or at dosing intervals that are longer than the duration of action of the drug.[7] Pseudo-addictive behaviors are more likely to occur in patient care settings where health care professionals are inadequately trained in pain management and the rational use of opioids. The appropriate clinical response to pseudo-addictive behaviors is to reassess the patient's pain and to treat the pain adequately.

--Sophie M. Colleau, PhD and David E. Joranson, MSSW


1. Portenoy RK. Opioid tolerance and responsiveness: Research findings and clinical observations. In: Gebhart GF, Hammond DL, Jensen TS (eds) Proceedings of the 7th world congress on pain. Seattle: IASP Press, 1994: 595-619.

2. Brescia FJ, Portenoy RK, Ryan M, et al. Pain, opioid use, and survival in hospitalized patients with advanced cancer. J Clin Oncol 1992; 10: 149.

3. Schug SA, et al. A long-term survey of morphine in cancer pain patients. J Pain Symptom Manage 1992; 7: 259-266.

4. Von Roenn JH et al. Physician attitudes and practice in cancer pain management: A survey from the Eastern Cooperative Oncology Group. Ann Intern Med 1993; 119: 121-126.

5. Waller A, Caroline NL. Handbook of palliative care in cancer. Butterworth-Heinemann: Boston, 1996.

6. O'Brien CP. Drug addiction and drug abuse. In: Goodman and Gilman's The pharmacological basis of therapeutics. 9th edition. New York: McGraw Hill, 1996: 557-569.

7. Weissman DE, Dahl JL, Dinndorf PA. Handbook of cancer pain management. 5th edition. Madison, WI: WCPI, 1996.

8. American Pain Society. Principles of analgesic use in the treatment of acute pain and cancer pain. Glenview, IL: APS, 1992.

9. Weissman DE, Haddox JD. Opioid pseudo-addiction - an iatrogenic syndrome. Pain 1989; 36: 363-366.