Learning Objectives

By the end of this topic, the student should be able to:

  • Describe how opioid tolerance and dependence develop and why withdrawal symptoms occur
  • Recognize the signs and symptoms of opioid withdrawal
  • Describe the pharmacological agents used to treat opioid withdrawal symptoms
  • Describe the role of opioid withdrawal in drug-seeking and unregulated opioid use

Key Concepts

  • Continued use of opioids can result in tolerance. A person may need to use an increasing amount of an opioid to obtain the same effect
  • Continued use of opioids can result in dependence. An opioid-dependent person will experience symptoms of withdrawal if opioids are stopped abruptly
  • Signs and symptoms of withdrawal include but are not limited to muscle aches, diarrhea, nausea and vomiting, shivering/goose bumps, yawning, sweating, anxiety, restlessness, sneezing, rapid heart rate, sleep disturbances
  • For many patients, symptoms of withdrawal may occur prior to initiation of opioid agonist therapy. Additional pharmacotherapies for withdrawal management include both prescription and over-the-counter drugs
  • The symptoms of opioid withdrawal can result in further prescription of the opioid, diverted opioid prescription, and unregulated opioid use

Tolerance and Dependence

The human body has its own, natural opioid system that works to regulate pain, mood, the GI tract, and many other functions.

Endogenous opioids are peptides that naturally occur in the body. They include several types of endorphins, enkephalins, and dynorphins that bind and activate opioid receptors.

Flow chart of endogenous opioid subgroups with focus on endorohins.

Flow chart with Endogenous Opiods at the top. Endogenous Opioids flows down to: Endorphins, Enkephalins, Dynophins, Endomorphins, Orphanin-FQ/Nociceptin (the last four are in a different colour). Endorphins flows down to β-endorphin, Endorphin-1, Endorphin-2.

Adapted from RCarstairs. (2015). Endogenous Opioids-Endorphins Schematic [Image]. Wikimedia. https://commons.wikimedia.org/wiki/File:Endogenous_Opioids-Endorphins_Schematic.png and licensed under CC BY-SA 4.0. Colours changed.

The Opioid System’s Natural Balance

Like all systems in the body, the opioid system is constantly fine-tuned: if the system becomes over-activated, the body takes steps to reduce this activity, and if the system is down-regulated, the body takes steps to increase activity.

What Happens When Someone Takes Opioids?

When exogenous opioids (i.e., opioids from an external source) are taken, the endogenous opioid system reacts by reducing its activity. This includes reducing the production of endogenous opioid peptides reducing the number of active opioid receptors.

  • At this point, the body has begun to adapt to the presence of the exogenous opioid

As the body adapts, tolerance can occur: the person needs more and more of the drug to produce the same effect.

  • With continued use, the body’s opioid system activity may be further and further impaired
  • Eventually, endogenous opioid system activity is reduced to the point that the body becomes reliant on continued exogenous opioids. This is called opioid dependence.

Withdrawal

Once a person is dependent on opioids, they will experience symptoms of opioid withdrawal if they stop taking opioids. Symptoms include:

Man sitting cross-legged on bed in a darkened room, head held in his hands.

Tzido/iStock

  • Muscle aches and weakness
  • Diarrhea and stomach cramps
  • Nausea and vomiting
  • Shivering/goose bumps
  • Yawning
  • Sweating, changes in body temperature
  • Anxiety
  • Restlessness
  • Sneezing and runny nose
  • Rapid heart rate
  • Sleep disturbances

When these symptoms occur, they are readily reversed by additional doses of an opioid.

Withdrawal severity is assessed clinically using the Clinical Opiate Withdrawal Scale (COWS).

See an example from the University Health Network: Clinical Opiate Withdrawal Scale (COWS).

Withdrawal Management

In addition to opioid agonist treatment (OAT), non-opioids are also used to manage the symptoms of opioid withdrawal. These include:

Healthcare practitioner showing client a blister pack of pills.

SARINYAPINNGAM/iStock

  • Clonidine, and alpha2-adrenergic receptor agonist, for anxiety
  • Quetiapine, an atypical antipsychotic, for anxiety
  • Trazodone, an antidepressant and antihistamine, for sleep
  • Ibuprofen, a cyclo-oxygenase inhibitor, for pain
  • Dimenhydrinate, an antihistamine, for nausea
  • Ondanestron, a serotonin blocker, for nausea
  • Loperamide, a peripheral opioid, for diarrhea

In addition to the agents listed above, other drugs may also be used to treat specific withdrawal symptoms.

In many cases, these drugs will be prescribed or used in a medical setting. However, individuals may obtain these and other drugs (e.g., benzodiazepines) to self-medicate withdrawal symptoms.

Withdrawal and Continued Opioid Use

Avoiding withdrawal symptoms is one of the primary motivators for continued opioid use. Individuals trying to avoid withdrawal symptoms and those experiencing withdrawal symptoms may self-medicate symptoms of withdrawal with opioids. In order to obtain opioids for this purpose, they may:

  • try to obtain prescription opioids, including seeking out prescriptions from multiple prescribers,
  • purchase diverted prescription opioids, including diverted buprenorphine-naloxone (a drug used as an opioid agonist treatment),
    • Recall: “diverted” refers to a prescription drug in the hands of someone other than the intended recipient.
  • purchase unregulated opioids - this poses a risk of overdose if the individual has limited experience with non-pharmaceutical grade opioids,

In addition to self-medicating symptoms of withdrawal with opioids, individuals may self-medicate with the agents listed for withdrawal management, via prescription, or purchasing from diverted or unregulated sources.

Stop and Think

Now that you have reviewed this content, take a moment to consider the following:

How would you explain opioid tolerance, dependence, and withdrawal to a patient, client, or person you are working with?

Some patients, opioid users, health professionals, and researchers have called for a “safe supply” of regulated, pharmaceutical-grade opioids that can be readily accessed by opioid users.

  • Would you describe this as a harm reduction strategy? What makes/doesn’t make this a harm reduction strategy?
  • Do you agree or disagree with a “safe supply” of opioids? Why or why not?

Consider the information described above. We encourage you to discuss these questions with professionals and those with lived experiences.

Questions

To avoid withdrawal symptoms, what might an individual do?

References

Brunton, L. L., Hilal-Dandan, R., & Knollmann, B. C. (2008). Goodman and Gilman’s: The pharmacological basis of therapeutics (13th ed.). McGraw-Hill Education.

DiPiro, J. T., Yee, G. C. L., Posey, M., Haines, S. T., Nolin, T. D., & Ellingrod, V. (2019). Pharmacotherapy: A pathophysiologic approach (11th ed.). McGraw-Hill Education.

Katzung, B. G. (2018). Basic and clinical pharmacology (14th ed.). McGraw-Hill Education.

Mateau-Gelabert, P., Jessell, L., Goodbody, E., Kim, D., Gile, K., Teubl, J., Syckes, C., Ruggles, K., Lazar, J., Friedman, S., & Guarino, H. (2017). High enhancer, downer, withdrawal helper: Multifunctional nonmedical benzodiazepine use among young adult opioid users in New York City. International Journal of Drug Policy, 46, 17–27.

Weiss, R. D., Sharpe Potter, J., Griffin, M. L., McHugh, R. K., Haller, D., Jacobs, P., Gardin II, J., Fischer, D., & Rosen, K. D. (2014). Reasons for opioid use among patients with dependence on prescription opioids: The role of chronic pain. Journal of Substance Abuse Treatment, 47, 140–145.

Wesson, D. R., & Ling, W. (2003). The clinical opiate withdrawal scale (COWS). Journal of Psychoactive Drugs, 35, 253–259.