Defining opioid tolerance and dependency

With Dr César Margarit Ferri  |  17 Feb 2015  |  Print

Defining opioid tolerance and dependency

Dr César Margarit Ferri is chief of the pain unit at the anesthesiology-critical care-pain medicine department, Alicante Hospital, Alicante, Spain.

Although opioids have been used to treat patients with chronic cancer and non-cancer pain for many years, when opioids are initiated it can highlight the lack of knowledge regarding some aspects of opioid therapy for both physicians and patients. One of the most important areas is the confusion surrounding the definitions of opioid tolerance and opioid dependency.

Existing criteria which relate to substance dependence (the term used in preference to ‘addiction’) have poor applicability when patients are using opioids for pain relief, and the criteria have acted as a source of concern to physicians, patients and carers.[1]


Substance abuse problems can be divided into two categories: dependence and abuse. Addiction and physical dependence are not the same; any patient taking opioids has the potential to develop physical dependence and may suffer withdrawal symptoms upon the discontinuation of the opioid.[2]

Tolerance is defined as a loss of analgesic potency that leads to ever-increasing dose requirements and decreasing effectiveness over time.[3] Exposure to a drug (the opioid) induces changes that result in a diminution of one or more of the drug’s effects over time. There are two types of tolerance: innate (genetically determined) and acquired (pharmacokinetic, pharmacodynamic and learned). In contrast to analgesic tolerance, tolerance to opioid-induced side-effects is a desirable consequence of long-term treatment, facilitating upward dose titration to attain satisfactory pain relief.[4]

Addiction is a more complicated illness: it is a primary, chronic, neurobiological disease with genetic, psychosocial and environmental factors influencing its development and manifestation.2 Addiction is comprised of four core elements (the four C’s):[2]

  • compulsive use,
  • inability to control the quantity used,
  • craving the psychological drug effects, and
  • continued use of the drug despite its adverse effects.

Addiction should not be confused with physical dependence which is a drug class-specific withdrawal syndrome (for example, pain, insomnia, tachycardia, tachypnea and diarrhea) that is produced by the abrupt cessation of a drug, a rapid dose reduction, a decreasing blood level of the drug and/or the administration of an antagonist.[2] In the past, patients who had non-optimal pain control using medication and who instigated unauthorized dose escalation were misdiagnosed as addicts (pseudo-addiction); the difference is that when pain is controlled this behavior disappears.[2]

Table. Principles of opioid therapy

Careful selection of patients Screening tools/risk factors
Individualized information Informed consent
Caution in dose escalation,
follow guideline recommendations
Monitoring, urine tests
Taper and discontinue if no benefit Follow up
Detect misuse, abuse and tolerance Referral to secondary care if needed


Patient management

When prescribing opioids, doctors and patients should discuss the goals of treatment, what a successful opioid trial outcome would be, what an unsuccessful trial looks like, as well as the further options available if the trial is unsuccessful.[5] The aim is to alleviate patient fears including ‘What  happens if I’m opioid tolerant?’ and ‘Will I become an addict?’. This kind of comprehensive assessment is appreciated by patients, providing an understanding of the goals of treatment, the secondary effects and the monitoring program.[5]


Physicians should treat their patients according a balanced multi-modal treatment strategy where established monitoring and global follow up are mandatory.[6] The risks and benefits of opioid therapy should be adequately explained to both patients and their carers. Three important principles to follow are:[7]

  • titration: titrate against analgesic response and side-effects (with regular assessment),
  • tailoring: treatment should be individualized, and
  • tapering: controlled decrease of any opioid treatment which does not improve pain despite adequate trial.

Screening tools may be useful in identifying patients with risk factors for addiction who will need closer follow-up.[7]


1. Stannard C. All Party Parliamentary Group on Drug Misuse Inquiry Response on behalf of the British Pain Society. Risk of addiction to opioids prescribed for pain relief. British Pain Society, London, 2007.
2. Jan SA. Introduction: landscape of opioid dependence. J Manag Care Pharm 2010;16(1 Suppl B):S4-S8.
3. Benyamin R, Trescot AM, et al. Opioid complications and side effects. Pain Physician 2008;11(2 Suppl):S105-S120.
4. Adriaensen H, Vissers K, et al. Opioid tolerance and dependence: an inevitable consequence of chronic treatment? Acta Anaesthesiol Belg 2003;54:37-47.
5. Pohl M, Smith L. Chronic pain and addiction: challenging co-occurring disorders. J Psychoactive Drugs 2012;44:119-124.
6. Snidvongs S, Mehta V. Recent advances in opioid prescription for chronic non-cancer pain. Postgrad Med J 2012;88:66-72.
7. Kahan M, Wilson L, et al. Canadian guideline for safe and effective use of opioids for chronic noncancer pain: clinical summary for family physicians. Part 2: special populations. Can Fam Physician 2011;57:1269-1276.