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by Patrick G. O’Connor, MD, MPH

Opioids are euphoriants that, in high doses, cause sedation and respiratory depression. Respiratory depression can be managed with specific antidotes (eg, naloxone) or with endotracheal intubation and mechanical ventilation. Withdrawal manifests initially as anxiety and drug craving, followed by increased respiratory rate, diaphoresis, yawning, lacrimation, rhinorrhea, mydriasis, and stomach cramps and later by piloerection, tremors, muscle twitches, tachycardia, hypertension, fever, chills, anorexia, nausea, vomiting, and diarrhea. Diagnosis is clinical plus with urine tests. Withdrawal can be treated by substitution with a long-acting opioid (eg, methadone) or buprenorphine (a mixed opioid agonist-antagonist).

“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 Geriatrics Essentials : Opioid Analgesics).


There are 3 main opioid receptors: delta, kappa, and mu. They occur throughout the CNS 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 GI tract.

Opioid receptors are stimulated by endogenous endorphins, which generally produce analgesia and a sense of well-being. Opioids are used therapeutically primarily as analgesics. Opioids vary in their receptor activity, and some (eg, buprenorphine) have combined agonist and antagonist actions. Compounds with pure antagonist activity (eg, naloxone, naltrexone) are available.

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 min after IV injection, 10 to 15 min after nasal insufflation, and 90 to 120 min after oral ingestion, although time to peak effects and duration of effect vary considerably depending on the specific drug.

Chronic effects

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 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.

Long-term effects of the opioids themselves are minimal; even decades of methadone use appear to be well tolerated physiologically, although some long-term opioid users experience chronic constipation, excessive sweating, peripheral edema, drowsiness, and decreased libido. However, many long-term users who inject opioids have adverse effects from contaminants (eg, talc) and adulterants (eg, nonprescription stimulant drugs) and cardiac, pulmonary, and hepatic damage due to infections such as 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 physical dependence in the fetus (see Opioids).

Symptoms and Signs

Acute effects

Acute intoxication is characterized by euphoria and drowsiness. Mast cell effects (eg, flushing, itching) are common, particularly with morphine. GI effects include nausea, vomiting, decreased bowel sounds, and constipation.

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.

Normeperidine, a metabolite of meperidine, accumulates with repeated use (including therapeutic); it stimulates the CNS and may cause seizure activity.

Serotonin syndrome ( Serotonin Syndrome) occasionally occurs when fentanyl, meperidine, or oxycodone is taken concomitantly with other drugs that have serotonergic effects (eg, SSRIs, monoamine oxidase inhibitors). This syndrome consists of one or more of the following:

  • Hypertonia

  • Tremor and hyperreflexia

  • Spontaneous clonus

  • Inducible clonus plus agitation or diaphoresis

  • Ocular clonus plus agitation or diaphoresis

  • Temperature > 38° plus ocular or inducible clonus


The withdrawal syndrome usually includes symptoms and signs of CNS hyperactivity. Onset and duration of the syndrome depend on the specific drug and its half-life. Symptoms may appear as early as 4 h after the last dose of heroin, peak within 48 to 72 h, and subside after about a week. Anxiety and a craving for the drug are followed by increased resting respiratory rate (> 16 breaths/min), 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.

The withdrawal syndrome in people who were taking methadone (which has a long half-life) develops more slowly and may be less acutely severe than heroin withdrawal, although users may describe it as worse. Even after the withdrawal syndrome remits, lethargy, malaise, anxiety, and disturbed sleep may persist up to several months. Drug craving may persist for years.


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


  • Supportive therapy

  • For withdrawal, sometimes drug therapy (eg, with an opioid agonist, opioid agonist-antagonist, opioid antagonist, or clonidine)

Toxicity or overdose

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

  • Naloxone 0.4 mg IV

  • Sometimes endotracheal intubation

Patients with spontaneous respirations can be treated with an opioid antagonist, typically naloxone 0.4 mg IV (for children < 20 kg, 0.1 mg/kg); naloxone has no agonist activity and a very short half-life (see Table: Symptoms and Treatment of Specific Poisons). Naloxone rapidly reverses unconsciousness and apnea due to an opioid in most patients. If IV access is not immediately available, IM or sc administration is also effective. A 2nd or 3rd dose can be given if there is no response within 2 min. Almost all patients respond to three 0.4-mg doses. If they do not, the patient’s condition is unlikely to be due to an opioid overdose, although massive opioid overdose may require higher doses of naloxone. Because some patients become agitated, delirious, and combative as consciousness returns and because naloxone precipitates acute withdrawal, soft physical restraints should be applied before naloxone is given. To ameliorate withdrawal in long-term users, some experts suggest titrating very small doses of naloxone (0.1 mg) when the clinical situation does not require emergency total reversal.

Apneic patients require endotracheal intubation. These patients should probably not receive total naloxone reversal because they may become agitated and belligerent when they suddenly regain consciousness.

In general, patients treated for overdose should be hospitalized and observed for at least 24 h because the duration of action of naloxone is less than that of some opioids, and overdose symptoms can redevelop. Respiratory depression may recur within several hours, especially with methadone or sustained-released oxycodone or morphine tablets. If respiratory depression recurs, naloxone should be readministered at an appropriate dose. Continuous naloxone infusion may be helpful for recurrent respiratory depression; two thirds of the dose that relieved respiratory depression is given hourly. Patients should be observed until no naloxone pharmacologic activity is present and they have no opioid-related symptoms. The serum half-life of naloxone is about 1 h, so an observation period of 2 to 3 h after use of naloxone should clarify disposition. The half-life of IV heroin is relatively short, and recurrent respiratory depression after naloxone reversal of IV heroin is rare.

Acute pulmonary edema is treated with supplemental O 2 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”)

  • Substitution with methadone or buprenorphine

  • Clonidine to relieve symptoms

  • Long-term support and possibly naltrexone

The withdrawal syndrome is self-limited and, although severely uncomfortable, is not life threatening. Minor metabolic and physical withdrawal effects may persist up to 6 mo. 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. Clonidine can provide some symptom relief during withdrawal.

Methadone substitution is the preferred method of managing opioid withdrawal for more seriously addicted patients because at appropriate doses, it has a long half-life and less profound sedation and euphoria. Any physician can initiate methadone substitution during hospitalization or for 3 days in an outpatient setting, but further treatment is continued in a licensed methadone treatment program. Methadone is given orally in the smallest amount that prevents severe but not necessarily all symptoms of withdrawal. Typical dose range is 15 to 30 mg once/day; doses 25 mg can result in dangerous levels of sedation in patients who have not developed tolerance. 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%/day unless the decision is made to continue the drug at a stable dose (methadone maintenance— Maintenance). During tapering of the drug, patients commonly become anxious and request more of the drug. Methadone withdrawal for addicts who have been in a methadone maintenance program may be particularly difficult because their dose of methadone may be as high as 100 mg once/day; in these patients, the dose should be gradually reduced to 60 mg once/day over several weeks before attempting complete detoxification.

Methadone has been reported to be associated with QTc prolongation and serious arrhythmias including torsade de pointes. Thus, it should be used very carefully with appropriate patient evaluation and monitoring during initiation and dose titration.

Buprenorphine , a mixed opioid agonist-antagonist usually given sublingually, also has been successfully used in withdrawal. It is available in a combination formulation with naloxone to prevent diversion to IV use. The first dose is given when the first signs of withdrawal appear. The dose needed to effectively control severe symptoms is titrated as quickly as possible; sublingual doses of 8 to 16 mg/day are typically used. Buprenorphine is then tapered over several weeks. Protocols for using buprenorphine for detoxification or maintenance therapy are available at the US Department of Health and Human Services web site US Department of Health and Human Services web site.

Clonidine , a centrally acting adrenergic drug, can suppress symptoms and signs of opioid withdrawal. Starting dosages are 0.1 mg po q 4 to 6 h and may be increased to 0.2 mg po q 4 to 6 h as tolerated. Clonidine can cause hypotension and drowsiness, and its withdrawal may precipitate restlessness, insomnia, irritability, tachycardia, and headache.

Rapid and ultrarapid protocols have been evaluated for managing withdrawal and detoxification. In rapid protocols, combinations of naloxone, nalmefene, and naltrexone are used to induce withdrawal, and clonidine and various adjuvant drugs are used to suppress withdrawal symptoms. Some rapid protocols use buprenorphine to suppress opioid withdrawal symptoms. Ultrarapid protocols may use large boluses of naloxone and diuretics to enhance excretion of the opioids while patients are under general anesthesia; these ultrarapid protocols are not recommended because they have a high risk of complications and no substantial additional benefit.

Clinicians must understand that detoxification is not treatment per se. It is only the first step and must be followed by an ongoing treatment program, which may involve various kinds of counseling and possibly nonopioid antagonists (eg, naltrexone).

Opioid Abuse and Rehabilitation

Heroin is commonly abused, and abuse of prescription analgesic opioids (eg, morphine, oxycodone, hydrocodone, fentanyl) is increasing; some of the increase is due to people who began taking them for legitimate medical purposes. Patients with chronic pain requiring long-term use should not be routinely labeled addicts, although they commonly have tolerance and physical dependence.


  • For severe, relapsing dependence, maintenance preferred to opioid withdrawal

  • For maintenance, buprenorphine or methadone

  • Ongoing counseling and support

Physicians must be fully aware of federal, state, and local regulations concerning use of an opioid drug to treat an addict. To comply, physicians must establish the existence of physical opioid dependence. In the US, treatment is further complicated by negative societal attitudes toward addicts (including the attitudes of law enforcement officers, physicians, and other health care practitioners) and toward treatment programs, which some view as abetting drug consumption. In most cases, physicians should refer opioid-dependent patients to specialized treatment centers. If trained to do so, physicians may provide office-based treatment for selected patients. In European countries, access to methadone or buprenorphine maintenance programs and alternative maintenance strategies is easier, and the stigma attached to prescribing psychoactive drugs is less.


Long-term maintenance using an oral opioid such as methadone or buprenorphine (an opioid agonist-antagonist) is an alternative to opioid substitution with tapering. Oral opioids suppress withdrawal symptoms and drug craving without providing a significant high or oversedation and, by eliminating the supply problems of addicts, enable them to be socially productive. In the US, thousands of opioid addicts are in licensed methadone maintenance programs. For many, such programs work. However, because the participants continue to take an opioid, many people in society disapprove of these programs.

Eligibility criteria include the following:

  • A positive drug screen for opioids

  • Physical dependence for > 1 yr of continuous opioid use or intermittent use for even longer

  • Evidence of withdrawal or physical findings confirming drug use

Clinicians and patients need to decide whether a withdrawal (detoxification) or opioid maintenance approach is indicated. Generally, patients with severe, chronic, relapsing dependence do much better with opioid maintenance. Withdrawal and detoxification, although effective in the short term, have poor outcomes in patients with severe opioid dependence. Whichever course is chosen, it must be accompanied by ongoing counseling and supportive measures.

Methadone is commonly used. Physicians can begin the substitution, but then use of methadone must be supervised in a licensed methadone treatment program.

Buprenorphine is being used increasingly for maintenance. Its effectiveness is comparable to that of methadone, and because it blocks receptors, it inhibits concomitant illicit use of heroin or other opioids. Buprenorphine can be prescribed for office-based treatment by specially trained physicians, including primary care physicians, who have received the required training and have been certified by the federal government. The typical dosage is an 8- or 16-mg sublingual tablet once/day. Many patients prefer this option because it eliminates the need for attending a methadone clinic. Buprenorphine is also available in combination with naloxone; the addition of naloxone may further discourage illicit opioid use. The combination formulation is used in office-based treatment.

Naltrexone, an opioid antagonist, blocks the effects of heroin. The usual dosage is 50 mg po once/day or 350 mg/wk po in 2 or 3 divided doses. A once-monthly depot IM formulation is also available. Because naltrexone is an opioid antagonist and has no direct agonist effects on opioid receptors, naltrexone is often unacceptable to opioid-dependent patients, especially those who have chronic, relapsing opioid dependence. For such patients, opioid maintenance treatment is much more effective. Naltrexone may be useful for patients with less severe dependence, early-stage opioid dependence, and strong motivation to remain abstinent. For example, opioid-dependent health care practitioners whose future employment is at risk if opioid use persists may be excellent candidates for naltrexone.

Levomethadyl acetate (LAAM), a longer-acting opioid related to methadone, is no longer used because it causes QT-interval abnormalities in some patients. LAAM could be used only 3 times/wk, thereby reducing the expense and problems of daily client visits or take-home drugs. A dose of 100 mg 3 times/wk is comparable to methadone 80 mg once/day.


Most treatment of opioid dependence occurs in outpatient settings, typically in licensed opioid maintenance programs but increasingly in physician’s offices.

The therapeutic community concept, pioneered by Daytop Village and Phoenix House, involves nondrug treatment in communal residential centers, where drug users receive training, education, and redirection to help them build new lives. Residency is usually 15 mo. These communities have helped, even transformed, some users. However, initial dropout rates are extremely high. Questions of how well these communities work, how many will be opened, and how much funding society will give remain unanswered.

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