Narcotic Overdose and Withdrawal

I. What every physician needs to know.

Narcotics, also referred to as opioids, encompass a class of drugs commonly abused in the United States. Opioids are also frequently encountered in the hospitalized patient, being only second to alcohol in drug related admissions. Opioid dependence and abuse is often a chronic, relapsing disorder that is amiable to medical treatment. The core feature of dependence is compulsive drug use, such that other aspects of mental and physical life are ignored or become less important over time. The characteristics of abuse include the continued use of the substance despite harmful consequences. Although heroin is most frequently associated with drug abuse and dependence, the abuse of prescription opioids is steadily increasing. Between 2013 and 2014, the age- adjusted rate of death involving natural and semisynthetic opioid pain relievers, heroin, and synthetic opioids, other than methadone (e.g., fentanyl), increased by 9%, 26%, and 80%, respectively.

Although there are five types of opioid receptors in mammals, virtually all opioid abuse and dependence seen in clinical practice is associated with drugs that are μ receptor agonists. Activation of the μ receptors leads to a feeling of well-being and euphoria via the dopaminergic mesolimbic system. This pathway originates in the ventral tegmental area (VTA) of the midbrain and projects to the nucleus accumbens, where dopamine is released. The administration of μ-agonist opioids increases the activity of dopaminergic neurons by inhibiting ϒ-aminobutyric acid, which normally inhibits VTA activity.

Opioid withdrawal and intoxication are a normal consequence of regular opioid intake. The presentation of both opioid intoxication and withdrawal from opioids is widely variable. Withdrawal can present from minutes to days of cessation of an opioid or the administration of an antagonist and can have a number of physical and psychiatric manifestations. The treatment of either condition is also variable, although there are some standard approaches.

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II. Diagnostic Confirmation: Are you sure your patient has Narcotic Overdose and Withdrawal?

Intoxication or withdrawal from opioids is a clinical diagnosis which is based on a combination of patient history, physical exam findings, and laboratory studies. There are no specific radiologic or laboratory tests used for the diagnosis. Opioid intoxication is suspected in persons who present with signs and symptoms of opioid use who may or may not have a positive toxicology screen.

A. History Part I: Pattern Recognition:

Although heroin overdose deaths are common in the age range of 20- to 30-years, the majority of admissions in 2005 for heroin abuse were for those in the 50- to 54-year-old age group. Prescription opioid abuse, excluding methadone, was most common in the 20- to 29-year old age group.

The presentation of opioid intoxication or overdose can vary in severity and should be suspected in patients with a known history of opioid dependence or abuse, or in patients who present with a typical opioid toxidrome. Patients who are known chronic opioid users and have had a period of abstinence are at an increased risk of overdose. The presentation can be as severe as coma and severe respiratory depression, and as mild as impairment in attention. The typical signs related to opioid intoxication include slow pulse, low body temperature, pinpoint pupils, slurred speech, hypotension, sedation, slowed movements, and head nodding. Euphoria and calmness are also commonly seen in opioid intoxication.

Opioid withdrawal symptoms can be described as being the opposite of the acute agonist effect, and occur after cessation (or reduction) of an opioid after use has been heavy or prolonged or with the administration of an antagonist. Clinical features of withdrawal can be divided into four grades.

Grades one and two encompass the early stages of withdrawal (8-24 hours). In grade one, symptoms include lacrimation, rhinorrhea, diaphoresis, yawning, restlessness, and insomnia. Grade two symptoms become more pronounced and include mydriasis, piloerection, muscle twitching, myalgias, arthralgias, and abdominal pain. Grades three and four are considered fully developed withdrawal, occurring 1 to 3 days from last use, and characterized by tachycardia, hypertension, tachypnea, fever, anorexia, nausea, and extreme restlessness. These symptoms may also progress to diarrhea and/or vomiting, dehydration, hyperglycemia, hypotension, and a semi-fetal position.

The onset of withdrawal may be influenced by different patient-related and drug-related factors, but as a general rule, short-acting opioids withdrawal symptoms begin around 8-12 hours from last use, peaks around 2-3 days, and can last 7-10 days. For long acting opioids, such as methadone, the onset of withdrawal is delayed and generally occurs at 24-72 hours, peaks at 3-8 days, and can last for several weeks.

B. History Part 2: Prevalence:

Opioid addiction is common in the community dwelling population, with heroin having a 1.5% life time prevalence. The number of people who initiated misuse of prescription opioids has surpassed marijuana use. The face of opioid addiction is varied and it affects all genders, races, and socioeconomic classes; however, there have been proposed genetic, psychological, and social factors that may contribute to addiction.

More people died from drug overdoses in the United States in 2014 than during any previous year on record. From 2000 to 2014 nearly half a million persons in the United States died from drug overdoses. Opioids, primarily prescription pain relievers and heroin, are the main drugs associated with overdose deaths. The 2014 data demonstrate that the United States’ opioid overdose epidemic includes two distinct but interrelated trends; a 15-year increase in overdose deaths involving prescription opioid pain relievers and a recent surge in illicit opioid overdose deaths, driven largely by heroin.

Populations that are particularly at risk for heroin addiction include the homeless and people in correctional facilities. The mentally ill are also a population which the provider should identify as high risk. Recent reports reveal that 18% of Americans 18 years or older have experienced some form of mental illness in 2014. The likelihood of substance abuse in patients with mental illness is 27.6%, as compared to 13% in those without mental illness. Patient with a limited education are also at high risk for a substance abuse related admission, mainly those who left school before completing high school or receiving a general education development exam.

C. History Part 3: Competing diagnoses that can mimic Narcotic Overdose and Withdrawal.

In general, the diagnosis of opioid overdose or withdrawal is made when the symptoms are not due to a general medical condition or better explained by another mental disorder.

Opioid intoxication can be mimicked by any number of illicit or prescription drugs and in many cases, the clinical presentation overlaps. Virtually any condition that leads to a coma can be considered as a differential for the diagnosis of opioid overdose, and severe metabolic, infectious, and vascular diseases should be ruled out. A good history and physical exam is key in establishing the diagnosis. Naloxone can also be used to help confirm the diagnosis, however, its administration should be done with caution, particularly in postoperative patients with preexisting cardiovascular disease. Excessive reversal of analgesia has resulted in significant cardiovascular and pulmonary complications, which may lead to death.

Withdrawal from opioids can also mimic other withdrawal syndromes, and a detailed history and physical is crucial in the diagnosis.

D. Physical Examination Findings.

In addition to the physical exam findings mentioned earlier, attention should be paid to signs of chronic drug abuse such as “track marks”, nasal septal perforations, and signs of acute or chronic liver disease. Co-infections such as human immunodeficiency virus (HIV) or endocarditis should also be kept in mind. Consequences of intravenous drug abuse such as infections, venous scleroses, and lymph obstruction may lead to edema of the extremities. Repeated intramuscular injections, particularly with meperidine but also with other opioid analgesics, may result in rock hard subcutaneous indurations.

In opioid overdose, particular attention should be paid to the respiratory rate. A respiratory rate of 12 or less, with or without miosis and evidence of opioid abuse, is highly sensitive in predicting opioid overdose in the pre-hospital setting. When examining opioid overdose patients, hospitalists should evaluate for pulmonary edema or aspiration. A rectal and/or vaginal exam (when appropriate) should also be performed because of the risk of packing opioids, which can serve as a means to avoid legal action or transport illicit drugs. Muscles should be examined to evaluate for compartment syndrome resulting from rhabdomyolysis. A total body exam should be performed to evaluate for possible presence of one or more fentanyl patches.

E. What diagnostic tests should be performed?

Although opioid overdose and withdrawal for the most part is a clinical diagnosis, certain tests may be useful to obtain in the appropriate setting.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Laboratory studies are usually ordered based on the patient’s presentation or the type of opioid abused. In patients with opioid overdose, it is useful to obtain a basic metabolic panel to access for evidence of hypoglycemia or metabolic abnormalities. Given the frequency of co-ingestion and because some opioids are combined with acetaminophen, levels of acetaminophen should be checked. If there is a history of trauma, immobility, or if obvious bruising is present, creatine kinase levels should be measured.

In the case of opioid withdrawal, laboratory tests should be ordered depending on the patient’s presentation. For example, in severe vomiting ordering a basic metabolic panel may be useful.

Urine toxicology screening is often obtained but it should not be used to make the diagnosis of opioid withdrawal or overdose, as false positive and negatives are common. However, performing a urine toxicology test is useful in determining the presence of co-ingestion with non-opioid central nervous system depressants. Opioids detected on urine toxicology include morphine, heroin, codeine, and hydrocodone, and the test may be positive for 12-36 hours (methadone may be detected longer). A significant ingestion of poppy seeds may lead to a false positive test for opioids. Standard urine drug screens generally do not detect fentanyl and oxycodone, as these are synthetic opioids. Screening with a urine toxicology is preferred because of its ease of sampling, ease of use, and rapid results. In patients with suspected overdose and a negative urine screen it may be useful to test for synthetic opioids.

In intravenous drug users or those that snort cocaine via a straw, liver enzymes, hepatitis B and C panels, and an HIV test should be obtained.

Electrocardiograms (ECG) are obtained in patients with respiratory compromise to evaluate for myocardial ischemia. Certain opioids affect cardiac conduction as well; for example, methadone is known to cause QTc prolongation and propoxyphene can prolong the QRS complex.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There is a limited role for the use of imaging studies in either opioid overdose or withdrawal. Chest X-rays are useful in patients with abnormal breath sounds or respiratory distress as opioids are a known cause of non-cardiac pulmonary edema. Furthermore, a chest x-ray may reveal pulmonary fibrosis secondary to injection of material which may be contaminated with microcrystalline talc or cotton particulates.

Abdominal X-ray or computed tomography (CT) of the abdomen may be useful when there is a suspicion of body packing or stuffing. Body packing is used for transporting illegal drugs and body stuffing is when drugs are swallowed, usually to avoid detection by police. The latter has a higher likelihood of leaking the drug and is therefore more dangerous.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.


III. Default Management.

A. Immediate management.

Initial management of opioid overdose is directed at managing the patient’s airway. Mechanical ventilation may be sufficient to avoid death, however, intubation may be avoided with the use of an opioid antagonist. Naloxone, an opioid antagonist, is the drug of choice for opioid overdose and when given appropriately, is very effective. Patients who are to receive naloxone should be on 100% oxygen to avoid acute lung injury related to the patient’s hypercapnic state. The duration of naloxone’s action is about 60-90 minutes which is sufficient for most opioids. In opioid overdose with longer half life agents like methadone, repeated administrations of naloxone may be required.

Dosing can begin at 0.8 mg per 70 kg of body weight and repeated at 2-3 minute intervals, or can be based on the patients respiratory rate. In patients breathing spontaneously, dosing can begin at 0.05 milligrams (mg) intravenously (IV) and repeated every 2-3 minutes. Dosing for apneic patients can begin at 0.2-1 mg IV given at 2-3 minute intervals and naloxone can be started at 2 mg IV and titrated up as needed for patients with cardiopulmonary arrest.

In patients who have poor IV access intramuscular naloxone is available, although the onset of action is slower and duration is prolonged.

Intranasal naloxone has been found to be effective in the field when used by emergency responders in suspected opioid overdose.

Other management essentials include the discontinuation of all forms of opioids, including transdermal patches.

The large volume of distribution of opioids makes hemodialysis ineffective in removing significant amounts of the drug, thus it is not used for the management of overdose.

Co-morbid conditions should be addressed and supportive treatment initiated. Agent specific antidotes for co-ingestions should be used.

Special consideration should be given to patients with retained packets of opioids. For body packers with active bowel sounds and no signs of opioid toxicity from a leaking package, polyethylene glycol electrolyte solution may be given orally or per rectum to speed the passage of the packet. Contraindications for the use of polyethylene glycol include a lack of protective airway response, bowel obstruction or perforation, or otherwise hemodynamically unstable patients. Body stuffers can be observed for 6-12 hours to pass the content and treated with naloxone if needed.

The onset of opioid withdrawal is dependent on the half life of the opioid used. Opioid withdrawal is usually not life threatening, but not addressing withdrawal can lead to treatment non compliance.

After confirming the objective findings of opioid withdrawal such as elevated blood pressure or increased heart rate, the mainstay of therapy is reintroducing a long acting opioid agonist such as methadone. The starting dose is 10 mg oral or IV and may be administered every 4 hours at 10 mg as needed for 24 hours. Most patients do not need more then 40 mg in 24 hours. On day two, the amount given on the first day may be given as a once or twice a day dose. Titration can begin at 10% daily or 5 mg a day decrease by the third day.

Patients on chronic maintenance of methadone may have their usual dose restarted once confirmation is obtained from the dispenser. Given methadone’s long half life, missing one dose rarely leads to withdrawal.

Other agents used for withdrawal include buprenorphine, clonidine, and occasionally benzodiazepines. Methadone has a well-established and predictable dose that has been validated, and is therefore preferred over buprenorphine for inpatient withdrawal.

Agents such as α2 adrenergic antagonist, anti-diarrheal agents, benzodiazepines, and muscle relaxants may be used to alleviate symptoms. Clonidine at a dose of 0.1-0.3 mg three to four times a day can lessen symptoms such as sweating, cramps, and vomiting, but does not relieve cravings.

Tramadol has been used in an off-label manner for withdrawal, but it is not a controlled substance and cannot be used by a physician for this role.

Ultra rapid detoxification is not recommended given the risk associated with the procedure.

B. Physical Examination Tips to Guide Management.

Physical exam in patients treated for opioid intoxication should be focused on the patient’s respiratory status. Naloxone should be titrated to a respiratory rate of >12 breaths per minute as stated above. If there is no response to naloxone after 10 mg the diagnosis should be reconsidered, although intoxication with buprenorphine has a higher receptor affinity and may take higher amounts of naloxone for an appropriate response. Respiratory depression with buprenorphine is thought to have a ceiling.

Objective signs of opioid withdrawal include a pulse increase greater than 10 beats/min from baseline or a pulse greater than 90 as well as a blood pressure rise greater than 10 millimeters mercury (mmHg) from baseline or a blood pressure >160/95 mmHg. Administration of methadone should be given when 2 of 4 symptoms are present.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Patients should be followed clinically unless otherwise indicated.

D. Long-term management.

Long term management revolves around maintaining the patient drug free. Preferred methods include the use of a long acting opioid agonist in conjunction with psychosocial support. These non pharmacological approaches begin in the inpatient setting and include counseling services.

E. Common Pitfalls and Side-Effects of Management.

Methadone carries a black box warning with regards to QTc prolongation and the increased risk of torsade de pointes. Patients should be assessed for risk and informed of potential arrhythmia. Electrolytes should be corrected when appropriate. Torsade has been associated with doses >100 mg/day but have been observed at lower doses.

Although opioid withdrawal is usually not fatal, deaths have been reported during abrupt withdrawal in debilitated patients with other medical conditions. Frequently the deaths are iatrogenic.

A urine toxicology screen should not be used to dictate management or to make the diagnosis.

It is imperative to use 100% oxygen when using naloxone to avoid acute lung injury.

Caution should be used when administering naloxone in pregnancy and the risk and benefits of treatment should be weighed. If needed, the lowest possible dose should be administered to avoid withdrawal symptoms in mother or fetus.

The goal of naloxone treatment is not reversal of symptoms; it is to maintain appropriate spontaneous respiration.

Failure to address withdrawal symptoms can lead to patients leaving the hospital against medical advice (AMA).

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

In patients with renal insufficiency, the active metabolite of certain opioids will accumulate, leading to a prolonged half life and in turn a prolonged toxic period.

The methadone dose should be given at 50-75% in patients with creatinine clearance <10mL/minute. No adjustment is needed with buprenorphine.

B. Liver Insufficiency.

About 60-80% of opioid users who either inject or share straws have serologic evidence of hepatitis B or C in their system. Abnormal liver function test are common which is further complicated by the frequent co-ingestion of alcohol. It is important for hospitalists to be aware that cirrhosis is prevalent in opioid abusers because it can affect the duration of intoxication and impacts the use of opioids in withdrawal, as most are metabolized by the liver. Methadone is contraindicated in severe liver disease and buprenorphine should be used with caution.

C. Systolic and Diastolic Heart Failure.

Given the age distribution of some subsets of opioid abusers, heart failure is a relatively common finding that can be complicated by the drug use itself. Pulmonary hypertension and endocarditis are well documented complications of IV drug abuse. Care should be taken in these patients, particularly when using medications such as methadone or when intoxication with propoxyphene is suspected.

D. Coronary Artery Disease or Peripheral Vascular Disease.

Although there is no specific warning regarding coronary artery disease or peripheral artery disease, it is important to note some of the vascular effects of acute withdrawal can theoretically lead to cardiac issues. Care should be used when administering naloxone.

E. Diabetes or other Endocrine issues.

Opioids have well documented endocrinologic effects including hypogonadism and hypoglycemia. Given that severe hypoglycemia may mimic opioid overdose, blood sugars should be monitored.

F. Malignancy.

Certain malignancies related to complications from opioid abuse, such as from HIV or hepatitis C, are common. No specific adjustment to treatment is needed other than noted in other disease specific sections.

Tramadol has been associated with seizures so its use in opioid withdrawal should be avoided in patients at high risk for seizures.

G. Immunosuppression (HIV, chronic steroids, etc).

Opioids can produce immunosuppressive effects and are associated with conditions such as HIV with similar effects, however, no specific adjustment to the treatment of overdose or withdrawal is needed. There are some studies that suggest buprenorphine may have less of an effect on the immune system than full agonist drugs. This finding alone does not alter the recommendations.

H. Primary Lung Disease (COPD, Asthma, ILD).

Primary lung disease is common in opioid abusers from either tobacco abuse, complications of IV drug abuse, or related infections. This would be important in cases such as patients with tuberculosis where compliance with treatment may be affected if withdrawal from opioids is not addressed.

I. Gastrointestinal or Nutrition Issues.

Bowel irrigation for body packers should not be used in patients who have gastrointestinal pathology such as a bowel obstruction.

J. Hematologic or Coagulation Issues.

Abnormal blood counts or coagulation disorders are common, but their presence in acute overdose or withdrawal does not alter the treatment. There are a few exceptions however, such as when complications like intracranial bleeds mimic overdose.

K. Dementia or Psychiatric Illness/Treatment.

The presence of a co-morbid psychiatric condition has been associated with more severe substance abuse. Also, multiple drug interactions may occur in this population; for example, some opioids such as meperidine in combination with other drugs may lead to serotonin syndrome.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Sign out should focus on potential complications related to the type of opioid used or the current medications being used for treatment. For example, care should be given to sign out respiratory goal rates in patient’s receiving naloxone. Complications the patient may have experienced should be noted, particularly respiratory abnormalities in overdose such as hypoxia, aspiration, or acute lung injuries.

Other things to sign out include the risk of the patient leaving AMA if not addressed appropriately. Communication is important in avoiding this issue.

B. Anticipated Length of Stay.

Length of stay (LOS) varies and can be anywhere from 3-5 days for withdrawal. In cases of overdose the LOS depends on the agent used, co-morbidities, and any complications that may have arisen.

C. When is the Patient Ready for Discharge?

Patients are ready for discharge after an appropriate detoxification and when naloxone is no longer needed.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom.

Given the high rate of noncompliance, clinic appointments for general medical issues should be made for the patients. Also, appointments for follow up with counselors or therapist should be made. Return to the methadone clinic or other dispensaries should resume.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Prior to discharge, substance abuse related issues should be addressed including testing for HIV, Hepatitis B/C, tuberculosis, and syphilis. It should be noted there is a high rate of false positive tests for syphilis in IV drug users.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Tests should be determined based on any co-morbidities the patient may have related to their substance abuse, such as follow up liver enzymes or CD4 counts.

E. Placement Considerations.

Placement in an inpatient treatment program is the choice of the patient.

F. Prognosis and Patient Counseling.

Overall relapse is high in patients with opioid dependence but this is exacerbated in patients who undergo detoxification without subsequent follow up treatment.

The hospitalist should make it clear that treatment requires commitment to a long-term change in lifestyle and that the responsibility for making the changes falls on the patient.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

Age and disease specific vaccinations should be given per hospital protocol.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

The risk of readmission in persons who intentionally abuse opioids whether legally or illegally is high. One key step in preventing readmissions is involving psychiatry or chemical dependency departments early in the hospital stay in order to coordinate long term psychosocial care.

VII. What's the evidence?

Andrew, Kolodny, Andrew. “"The Prescription Opioid and Heroin Crisis: A Public Health Approach to an Epidemic of Addiction."”. Annu. Rev. Public Health. vol. 36. 2015. pp. 559-74.

Amato, L, Minozzi, S, Davoli, M, Vecchi, S. “Psychology and pharmacological treatments versus pharmacological treatments for opioid detoxification”. Cochrane Database of Systemic Reviews. 2011.

Stefanidou, M, Athanaselis, S, Spiliopoulou, C, Dona, A, Maravelias, C. “Biomarkers of opiate use”. Int J Clin Pract. vol. 64. 2010 Nov. pp. 1712-8.

Krupitsky, EM, Blokhina, EA. “Long-acting depot formulations of naltrexone for heroin dependence: a review”. Curr Opin Psychiatry. vol. 23. 2010 May. pp. 210-4.

McCance-Katz, EF, Sullivan, LE, Nallani, S. “Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review”. Am J Addict. vol. 19. 2010 Sep-Oct. pp. 458-9.

Wilcock, A, Beattie, JM. “Prolonged QT interval and methadone: implications for palliative care”. Curr Opin Support Palliat Care. vol. 3. 2009 Dec. pp. 252-7.

Aquina, CT, Marques-Baptista, A, Bridgeman, P, Merlin, MA. “OxyContin abuse and overdose”. Postgrad Med. vol. 121. 2009 Mar. pp. 163-7.

Tetrault, JM, O’Connor, PG. “Substance abuse and withdrawal in the critical care setting”. Crit Care Clin. vol. 24. 2008 Oct. pp. 767-88.

Benich, JJ. “Opioid Dependence”. Prim Care Clin Office Pract. vol. 38. pp. 59-70.

Boyer, EW. “Management of Opioid Analgesic Overdose”. N Engl J Med. vol. 367. 2012. pp. 146-155.

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