Opioid Toxicity and Withdrawal

ByGerald F. O’Malley, DO, Grand Strand Regional Medical Center;
Rika O’Malley, MD, Grand Strand Medical Center
Reviewed/Revised Dec 2022
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“Opioid” is a term for a number of natural substances (originally derived from the opium poppy) and their semisynthetic and synthetic analogues that bind to specific opioid receptors. Opioids, which are potent analgesics with a limited role in management of cough and diarrhea, are also common drugs of abuse because of their wide availability and euphoriant properties; see also Opioid Analgesics and Opioid Use Disorder and Rehabilitation.

Pathophysiology of Opioid Toxicity or Withdrawal

There are 3 main opioid receptors: delta, kappa, and mu. They occur throughout the central nervous system but particularly in areas and tracts associated with pain perception. Receptors are also located in some sensory nerves, on mast cells, and in some cells of the gastrointestinal tract.

Exogenous opioids can be taken by almost any route: orally, intravenously, subcutaneously, rectally, through the nasal membranes, or inhaled as smoke. Peak effects are reached about 10 minutes after IV injection, 10 to 15 minutes after nasal insufflation, and 90 to 120 minutes after oral ingestion, although time to peak effects and duration of effect vary considerably depending on the specific drug.

Chronic effects

Opioid tolerance develops quickly, with escalating dose requirements. Tolerance to the various effects of opioids frequently develops unevenly. Heroin users, for example, may become relatively tolerant to the drug’s euphoric and respiratory depression effects but continue to have constricted pupils and constipation.

A minor opioid withdrawal syndrome may occur after only several days use. Severity of the syndrome increases with the size of the opioid dose and the duration of dependence.

HIV infection and hepatitis B or C, which are spread by needle sharing and nonsterile injection techniques (see Injection Drug Use).


Use of opioids during pregnancy can result in opioid dependence in the fetus.

Symptoms and Signs of Opioid Toxicity or Withdrawal

Acute effects

Toxicity or overdose

The main toxic effect is decreased respiratory rate and depth, which can progress to apnea. Other complications (eg, pulmonary edema, which usually develops within minutes to a few hours after opioid overdose) and death result primarily from hypoxia. Pupils are miotic. Delirium, hypotension, bradycardia, decreased body temperature, and urinary retention may also occur.

Serotonin syndrome

  • Hypertonia

  • Tremor and hyperreflexia

  • Spontaneous, inducible, or ocular clonus

  • Diaphoresis and autonomic instability

  • Agitation

  • Temperature > 38° plus ocular or inducible clonus

Although rare among inhalational heroin users, spongiform leukoencephalopathy has been reported. The symptoms depend on the timing of presentation and may show motor restlessness, apathy, ataxia, or paralysis. The symptoms may resolve, or can progress to autonomic dysregulation and death.


The opioid withdrawal syndrome usually includes symptoms and signs of central nervous system hyperactivity. Onset and duration of the syndrome depend on the specific drug and its half-life. Symptoms may appear as early as 4 hours after the last dose of heroin, peak within 48 to 72 hours, and subside after about a week. Anxiety and a craving for the drug are followed by increased resting respiratory rate (> 16 breaths/minute), usually with diaphoresis, yawning, lacrimation, rhinorrhea, mydriasis, and stomach cramps. Later, piloerection (gooseflesh), tremors, muscle twitching, tachycardia, hypertension, fever and chills, anorexia, nausea, vomiting, and diarrhea may develop.

Opioid withdrawal does not cause fever, seizures, or altered mental status. Although it may be distressingly symptomatic, opioid withdrawal is not fatal.

Diagnosis of Opioid Toxicity or Withdrawal

  • Usually a clinical diagnosis

Diagnosis of opioid use is usually made clinically and sometimes with urine drug testing; laboratory tests are done as needed to identify drug-related complications. Drug levels are not usually measured.

Treatment of Opioid Toxicity or Withdrawal

  • Supportive therapy

Toxicity or overdose

Treatment to maintain the airway and support breathing is the first priority.

  • Sometimes endotracheal intubation

<Symptoms and Treatment of Specific Poisons

Acute pulmonary edema is treated with supplemental oxygen and often noninvasive or invasive modalities of breathing support (eg, bilevel positive airway pressure [BiPAP], endotracheal intubation).

Withdrawal and detoxification

Treatment may involve several strategies:

  • No treatment (“cold turkey”)

The opioid withdrawal syndrome is self-limited and, although severely uncomfortable, is not life threatening. Minor metabolic and physical withdrawal effects may persist up to 6 months. Withdrawal is typically managed in outpatient settings, unless patients require hospitalization for concurrent medical or mental health problems.

Options for management of withdrawal include allowing the process to run its course (“cold turkey”) after the patient’s last opioid dose and giving another opioid (substitution) that can be tapered on a controlled schedule.

, a partial opioid agonist—usually given sublingually—has been successfully used in treatment of withdrawal.

The Substance Abuse and Mental Health Services Administration (SAMHSA)

Symptom scales are available for estimating the appropriate dose. Higher doses should be given when evidence of withdrawal is observed. After the appropriate dose has been established, it should be reduced progressively by 10 to 20% each day unless the decision is made to continue the drug at a stable dose (). During tapering of the drug, patients commonly become anxious and request more of the drug.

Long QT Syndrome and Torsades de Pointes). Thus, it should be used very carefully with appropriate patient evaluation and monitoring during initiation and dose titration.

Rapid and ultrarapid protocols

More Information

The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

  1. Substance Abuse and Mental Health Services Administration (SAMHSA): US Department of Health agency that leads public health efforts to improve behavioral health and provides resources, including treatment locators, toll-free helplines, practitioner training tools, statistics, and publications on a variety of substance-related topics.

  2. Findtreatment.gov: Listing of licensed US providers of treatment for substance use disorders.

Drugs Mentioned In This Article
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