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Hydroxyzine for the Treatment of Acute Opioid Withdrawal: A 20-Year Clinical Experience

Lawrence Hauser, MD
Director of Psychiatric Education Austin Medical Education Program, Brackenridge Hospital Adjunct Faculty Austin Psychiatry Residency Program

Renu Anupindi, MD
Fellow, Child and Adolescent Psychiatry Training at Austin Psychiatry Residency Program

William Moore, LVN, BA
Intake Coordinator Travis County Correctional Facility Austin, Tex

Hydroxyzine, which has been available since 1955, has been used as an antihistamine, anxiolytic, sedative, and antiemetic. Sufficient research data support its efficacy in these areas. It has also been tried for the treatment of symptoms of withdrawal from alcohol and barbiturates, but only sporadically and backed by limited research. We have been using this agent for opioid withdrawal since 1985, first in prison populations and then in outpatient and hospital settings, with positive results. Hydroxyzine has effectively treated the withdrawal symptoms associated with a variety of opioids. Its safety, lack of effects on attention or memory, and absence of dependency, withdrawal, or abuse potential make it suitable for this purpose. Nevertheless, no research is available to back up our approach. This article is based on our long-term experience with this medication. We wish to create an awareness of this novel use of hydroxyzine and hope it would stimulate research to validate our clinical experience.

This article is based on our clinical experience for more than 20 years with hydroxyzine (Vistaril), according to which we have found this medication to be a safe and effective means of detoxification in patients withdrawing from opioids. Our clinical experience has involved structured facilities, such as jails, general hospital settings, and outpatient settings, where we have encountered large populations of opioid, heroin, and methadone users in need of detoxification and stabilization.

Practice points
The symptoms of opioid withdrawal can be very severe and contribute to the high rates of relapse.

The 5-day hydroxyzine protocol presented here provides an alternative for those who cannot use conventional medications for detoxification.

Hydroxyzine is cost- effective and lacks toxicity and physical dependence.

Each patient should be closely observed for the emergence of withdrawal from concomitant substance use.

The hydroxyzine protocol for opioid withdrawal was first used by a psychiatrist in the Travis County Jail in Austin, Texas, in 1982. Between 1985 and 2002 we used it in the Travis County Jail, which had a population of more than 2000 inmates. We have also used hydroxyzine to treat withdrawal symptoms at our county hospital. This protocol provides basic relief from most of the symptoms associated with opioid withdrawal, and it can be easily and safely used in general hospitals, correctional facilities, and outpatient clinics where a patient?s history and presentation can be unreliable.

However, this approach is not supported by clinical research or by the medical literature. We hope that this discussion will generate interest in validating our experience by clinical trials. A review of medical literature published during the past 2 decades revealed no references to hydroxyzine in association with opioid withdrawal. There are articles on its use for the treatment of anxiety and of combining it with opioids to decrease the opioid dosage and enhance pain control.1-3 More sophisticated substance abuse programs may use other methods of detoxification, often combining agents such as benzodiazepines, alpha-blockers, hypnotics, and opioid agonists/antagonists.

Table 1 lists opioids often encountered in clinical practice. According to our experience, many opioid users will have taken higher opioid doses or more drugs than they admit. Much of the discomfort associated with drug withdrawal is made up of anxiety, agitation, and insomnia. Hydroxyzine has been shown to be a safe treatment for anxiety1?and is frequently used in the elderly to treat both anxiety and insomnia.

For opioid withdrawal, we start with 50 to 100 mg of hydroxyzine, 4 times daily for 5 days. The drug is usually stopped after 5 days, although some patients may need a longer period of tapering. If patients become too sedated, twice-daily or 3-times-daily dosing can be used, or the doses can be reduced.

We have found this hydroxyzine protocol to be most useful in settings where other drugs are contraindicated because of underlying medical problems or unreliable medical histories. Hydroxyzine costs approximately 19??for a tablet, is easy to dispense by the nursing staff, and is easy to use by physicians of all levels of experience and specialties. In this age of managed care, where cost-effectiveness and efficiency are important, we believe that hydroxyzine represents a safe, efficacious, and inexpensive option for patients who are withdrawing from opioids.

Mechanisms of Opioid Withdrawal
Opioids exert their effects through ?-, k-,σ- ,δ- , and ε-endorphin receptors. The ?-receptors that mediate analgesia, respiratory depression, and constipation are also responsible for dependence. Although long-term use is associated with increased sensitivity of the dopaminergic, cholinergic, and serotonergic neurons, the effect of opioids on noradrenergic neurons is probably the primary mediator of withdrawal symptoms (Table 2). Short-term opioid use appears to decrease the activity of the noradrenergic neurons in the locus ceruleus, whereas long-term use activates a compensatory homeostatic mechanism within the neurons, leading to rebound hyperactivity with opioid withdrawal. The fact that clonidine (Catapres) - an α2-adrenergic receptor agonist that inhibits the release of norepinephrine - helps alleviate the symptoms of opioid withdrawal4supports the hypothesis of rebound norepinephrine hyperactivity.

Heroin, hydrocodone (eg, Lortab, Vicodin, Zydone), and methadone withdrawal are most frequently encountered in correctional facilities. With abrupt discontinuation, symptoms occur 6 to 8 hours after the last dose of heroin but may be delayed for up to 36 to 72 hours after the last dose of methadone.5 It is well established that opioid withdrawal is not fatal.6,7In adults withdrawing from opioids, the development of fever, altered mental status, and seizures is uncommon.

Detoxification
The goals of detoxification include managing the pain and intense discomfort and other physical signs of withdrawal, providing a safe transition from acute physiologic dependence, treating any medical problems, and setting the stage for long-term drug abuse interventions.

Established strategies for opioid detoxification include methadone, naltrexone HCl (ReVia), L-alpha-acetylmethadol (LAAM), clonidine, lofexidine (not available in the United States), and buprenorphine HCl (Subutex, Buprenex). Rapid and ultrarapid detoxi?fications under anesthesia are now possible, but these approaches are expensive and potentially dangerous.8,9

The role of methadone in relapse prevention has been well studied. Although any licensed physician can perform methadone detoxification in an inpatient setting, a program specially licensed for drug treatment is required for outpatient detoxification.7 Federal regulations mandate that only physicians with special registration from the Drug Enforcement Administration (DEA) can prescribe methadone for detoxification or maintenance on an outpatient basis.10This DEA registration is separate from the standard registration required for prescribing controlled substances and is contingent on compliance with DEA security and other regulations.

Available Opioid Detoxification Therapies
Methadone is a long-acting ?-agonist that blocks most withdrawal symptoms. Disadvantages are the need for long maintenance treatment, strict regulation, cost, and the development of dependence.

Naltrexone is an oral, long-acting opioid receptor antagonist that has been shown to be a successful, nonopioid treatment in certain populations. It works by blocking the opioid receptors; thus, if a person tries to ?get high,? the effect is blocked. This medication should only?be prescribed after a patient is opiate-free for 7 to 10 days, to avoid a precipitated withdrawal syndrome.

LAAM is a ?-agonist that is longer acting than meth?adone. It can be given 3 times weekly instead of every day. Its disadvantages include more side effects than methadone, strict regulation (it can be dispensed but not prescribed), availability only at federally regulated opioid treatment centers, and high cost.

Clonidine?acts on autoreceptors to inhibit hyperactive locus ceruleus neurons. It controls autonomic symptoms of withdrawal and shortens the duration of withdrawal. It does not, however, address craving and muscle aches. Sometimes hypotension can occur.

Lofexidine?is a structural analog of clonidine that has shown good results in Europe but is not available in the United States.

Buprenorphine has partial opioid agonist/antagonist activity. It is useful for acute withdrawal and, unlike clonidine, does not cause hypotension. Being a schedule III drug, it is subjected to fewer restrictions than the other opioid agents. It is also available for office-based practices under the Drug Addiction Treatment Act of 2000.

Clinical Pharmacology of Hydroxyzine
Hydroxyzine is a piperazine-derivative antihistamine, structurally similar to meclizine. It has no chemical relationship to phenothiazines, reserpine meprobamate, or the benzodiazepines.11 Although not a cortical depressant, it may suppress activity in certain key regions of the subcortical area of the central nervous system. Hydroxyzine is rapidly absorbed from the gastrointestinal tract; its clinical effects are evident within 15 to 30 minutes of oral administration.11

In addition to antihistaminic effects, hydroxyzine also has anxiolytic, analgesic, anticholinergic, anti?emetic, and skeletal muscle relaxant properties.11

Common use of hydroxyzine
Hydroxyzine is used to treat symptoms of anxiety and tension.11 It has also shown efficacy in the treatment of pruritus secondary to allergic conditions, as a preoperative sedative, and in the treatment of nausea and vomiting after general anesthesia.11 Its efficacy and safety in the treatment of generalized anxiety disorder have been well demonstrated in placebo-controlled clinical trials, which showed it was as effective as benzodiazepines.1,12

Antiemetic effects have been shown by the apomorphine test and the Veriloid test.11 It has been demonstrated that hydroxyzine in therapeutic dosages does not increase gastric secretion or acidity and in most cases provides antiemetic benefits. 13,14The drug has also been shown to be safe and effective for the treatment of nausea and vomiting in pregnancy15 and appears to have no human teratogenic potential.16 It is a category C medication. Nevertheless, the package insert notes pregnancy as a contraindication, indicating that more conclusive data are needed.Because of its antihistaminic and sedative properties, hydroxyzine, along with other members of its class, is often used in patients with cancer who suffer from insomnia.17 Other studies have shown increases in the duration of both slow-wave and rapid-eye-movement sleep.2

The efficacy of hydroxyzine as an adjuvant to opioids for pain control in patients with cancer has not been well studied. Some studies indicate that hydroxyzine in doses of at least 75 to 100 mg may provide adequate pain relief when given with a therapeutically effective dose of an opioid.3 Its use for barbiturate and benzodiazepine withdrawal has been reported in the literature, along with its lack of toxicity and absence of any physical dependence.18

Table 3 summarizes the effects of hydroxyzine in opioid withdrawal based on the authors? experience.

Safety and side effects
The side effects of hydroxyzine are mild and transient.11 Drowsiness and dry mouth are most frequently reported. At significantly higher-than-recommended dosages, stupor and convulsions may occur.11Recommended doses do not appear to produce clinically significant respiratory depression. However, the potentiating action of hydroxyzine must be considered when it is used in conjunction with central nervous system depressants, such as narcotics, nonnarcotic analgesics, or barbiturates. Thus, we recommend close follow-up and, if necessary, random drug screening in the outpatient setting to ensure patients are not using substances such as opioids or ethanol.

Clinical Experience with Hydroxyzine for Opioid Withdrawal
Our 20 years of experience with hydroxyzine for the acute treatment of heroin, methadone, and other opioid withdrawal has been encouraging. There have been no serious medical complications or deaths. Patient acceptance has been mixed. Most welcome the relief from nausea, anxiety, diarrhea, abdominal cramping, and vomiting. They respond well to the sedative effects of hydroxyzine and are able to sleep at night and feel less anxious during the day. Some inpatients who were using pain medications have been able to reduce or taper the dose of the opioids. However, some patients do not like hydroxyzine and claim that it does not help them. Many want a medication that will give them more of a ?high.? A few patients can have a paradoxical response to hydroxyzine and become stimulated. Some of these patients could be switched to diphenhydramine (eg, Benadryl), to which they would often respond.

Many of the patients we treat for opioid withdrawal present with unreliable medical histories and questionable symptoms and are using a combination of opioids and other nonprescribed drugs. Our experience has shown that this protocol offers a simple and safe method of withdrawal that alleviates the major symptoms and can be used when the true history and amount of previous drug use may be unknown. The protocol was originally developed at the Austin, Texas, Travis County Jail and has also been used at the Brackenridge Hospital (an acute care general hospital) in Austin for the past 20 years.

According to this treatment protocol, vital signs are recorded at the time of admission and then again in accordance with hospital protocol and as needed. Once a clear diagnosis of opioid withdrawal is established through the history, laboratory testing, and physical examination, the patient is started with a scheduled dose of oral hydroxyzine, 50 to 100 mg 4 times daily, or by intramuscular injection for patients unable to take pills. Hydroxyzine is discontinued at the end of the fifth day, although it may be tapered, beginning on the 6th day of treatment over the next 5 to 10 days if necessary. An as-needed dose of oral hydroxyzine, 100 mg every 12 hours, may be used in addition to the original dose in cases of extreme discomfort.

From January 2004 to July 2005, approximately 400 patients were treated for opioid withdrawal using this protocol at our local correctional facility. They most often reported using heroin and pain medications, such as hydrocodone, oxycodone (eg, Percocet, Percodan, OxyContin), or methadone. In addition to using the hydroxyzine protocol of 50 mg 4 times daily, patients had standing orders for acetaminophen (eg, Tylenol), promethazine (Phenergan), and bismuth subsalicylate (eg, Kaopectate) as needed. About 7% of the patients used the as-needed medications; the rest did well on the hydroxyzine protocol alone. None of the patients complained of persistent physical withdrawal symptoms after 5 days.

Selected Cases
The following selected cases reflect the varied settings in which the hydroxyzine protocol can be used. Table 4 describes 15 cases from our county jail between 2004 and 2005, demonstrating common scenarios.

Case 1: A 31-year-old man in the county jail had used heroin for many years. His last heroin dose was 2 days before his arrest. His chief complaints were chills, nausea, and muscle cramps. His vital signs were stable, and no other physical illness was identified. He was started on oral hydroxyzine, 50 mg 4 times daily for 5 days. His blood pressure and pulse were monitored twice daily. At the end of the 5 days, the patient reported no symptoms of opioid withdrawal and did not require any further treatment. He was released from medical follow-up.

Case 2: A 35-year-old man was brought to the emergency department of a general hospital with an occupational electrical injury. The psychiatric service was consulted because the patient reported that he had been taking 80 mg/day of methadone for the past 3 months and did not wish to return to this practice. On day 2 of hospitalization he was started on oral hydroxy?zine, 50 mg 4 times daily. He was also given Kaopectate for mild diarrhea and oral ibuprofen, 800 mg every 6 to 8 hours as needed, for pain from his injury. On day 3 he was feeling much better and had no symptoms of withdrawal. He was discharged with a prescription for oral hydroxyzine, 50 mg 4 times daily, which he self-tapered over the next week. At 5 months? follow-up, the patient had a negative urine drug screen and was participating in weekly psychotherapy sessions.

Case 3: A 30-year-old woman was seen as an outpatient. She had a history of taking 12 Vicodin tablets daily for the past 3 months. She had previously been treated for depression and cluster headaches with nortriptyline HCl (Aventyl, Pamelor). She had stopped taking Vicodin 2 days earlier and complained of craving for the drug, muscle cramps, increased anxiety, nausea, and chills. Her vital signs were stable. She was started on oral hydroxyzine, 100 mg 4 times daily. Nortriptyline was discontinued, and amitriptyline HCl, 50 mg every night, was started. Hydroxyzine was continued for 10 days, and the amitriptyline dosage was increased to 200 mg/day, leading to a resolution of her depression and headaches. She complained only of dry mouth. Her craving for Vicodin diminished after 6 weeks. She was followed monthly. Two years later she was still taking amitriptyline and was not using opioids.

Discussion
The 3 cases illustrate the ease and safety of hy?droxy?zine use for opioid withdrawal in a variety of settings. Hydroxyzine use does, however, potentiate the action of central nervous system depressants, such as narcotics, nonnarcotic analgesics, barbiturates, and alcohol. It is, therefore, crucial to obtain a thorough history from the patient, family members, or other reliable sources. A urine/serum drug screen should be done before initiating treatment, and the patient should be closely observed for the emergence of withdrawal from concomitant substance use. In addition to the scheduled doses of hydroxy?zine, as-needed doses of antidiarrheal and analgesics can be prescribed for severe gastrointestinal symptoms and myalgias.

In 2003, an estimated 3.7 million Americans said they had used heroin at some time in their lives, and more than 31 million had used narcotic pain relievers in a ?nonmedicinal? manner.19 In 2004, an estimated 6.2% of 10th graders and 9.3% of 12th graders reported using hydrocodone.20 Although opioid withdrawal is nonfatal, the symptoms can be very severe and often contribute to the high rates of relapse. Thus, medication-based treatments for opioid use include detoxification as well as maintenance.

A major frustration and limitation of all detoxification attempts of opioid users is the limited number of effective strategies that will enable patients to remain free of illicit drugs after detoxification. Methadone maintenance, and the more recent use of buprenorphine, have been found to be effective as maintenance treatments. Using maintenance therapy as a treatment option in addition to a detoxification strategy remains a viable alternative for many patients.

Other attempts at opioid detoxification have included bromide sleep treatment, hibernation therapy, and insulin-induced hypoglycemia - all of which were eventually found to be ineffective and dangerous.9 Reviews of ultrarapid detoxification under anesthesia suggest that it may be ineffective and unsafe.6,21 However, more recent rapid detoxification techniques using opioid antagonists/agonists, such as naloxone HCl (Narcan), naltrexone HCl, and buprenorphine have been successful in improving compliance with withdrawal treatment.9

Patients who are treated for opioid withdrawal must be referred to support groups, such as Narcotics Anonymous, chemical dependency group therapy, or individual therapy after the acute detoxification period is over. Treatment of comorbid psychiatric disorders is also important to improve the compliance of patients who have been using opioids to self-treat mood and anxiety-related disorders. Research supports the combination of various treatment modalities, including medication, group psychotherapy, and cognitive behavioral therapy, for better long-term outcomes in substance abuse patients.21

Conclusion
Our experience has shown that hydroxyzine is a safe and effective option for detoxification, with a favorable side-effect profile and low cost. It can be discontinued abruptly without causing rebound anxiety or withdrawal symptoms, and it has not been associated with dependency. Of course, other methods of detoxification are also useful. We hope that this protocol will provide physicians with another option for opioid detoxification and perhaps even stimulate more structured studies to substantiate our experience.

Self-assessment test
1.?All these features of opioid withdrawal begin within a few hours of the last dose, except:
A. Abdominal pain
B. Rhinorrhea
C. Lacrimation
D. Perspiration

2.?Which of these opioid detoxification treatments is most likely to cause hypotension?
A. Methadone
B. LAAM
C. Clonidine
D. Buprenorphine

3.?Hydroxyzine has beneficial effects on all these withdrawal features, except:
A. Diarrhea
B. Insomnia
C. Anxiety
D. Anorexia

4.?The following statements about hydroxyzine are correct, except:
A. It is only used in an inpatient setting
B. One tablet costs approximately 19?
C. It is not associated with dependency
D. Discontinuation does not produce withdrawal symptoms

5.?All these steps are part of the hydroxyzine opioid detoxification protocol, except:
A. Starting dosage of 50 to 100 mg 3 times daily
B. Hydroxyzine discontinuation after 5 days
C. Acetaminophen use as needed
D. Promethazine use as needed

(Answers at end of reference list)

References
1. Llorca PM, Spadone C, Sol O, et al. Efficacy and safety of hydroxy?zine in the treatment of generalized anxiety disorder: a 3-month double-blind study. J Clin Psychiatry. 2002;63: 1020-1027.

2. Ferreri M, Hantouche EG, Billardon M. Value of hydroxyzine in generalized anxiety disorder: controlled double-blind study versus placebo [in French]. Encephale. 1994;20:785-791.

3. Glazier HS. Potentiation of pain relief with hydroxyzine: a therapeutic myth? DICP. 1990;24:484-488.

4. Sadock BJ, Sadock VA, Kaplan HI, eds. Kaplan & Sadock?s Comprehensive Textbook of Psychiatry. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2004:1039-1043.

5. Olmedo R, Hoffman RS. Withdrawal syndromes. Emerg Med Clin North Am. 2000;18:273-288.

6. Gold MS. Opiate addiction and the locus coeruleus. The clinical utility of clonidine, naltrexone, methadone, and buprenorphine. Psychiatr Clin North Am. 1993;16:61-73.

7. Chiang WK, Goldfrank LR. Substance withdrawal. Emerg Med Clin North Am. 1990;8:613-631.

8. Collins ED, Kleber HD, Whittington RA, et al. Anesthesia-assisted vs buprenorphine- or clonidine-assisted heroin detoxification and naltrexone induction: a randomized trial. JAMA. 2005;294:903-913.

9. O?Connor PG. Methods of detoxification and their role in treating patients with opioid dependence [editorial]. JAMA. 2005;294:961-963.

10. Cooper JR. Including narcotic addiction treatment in an office-based practice. JAMA. 1995;273:1619-1620.

11.? Vistaril [package insert]. New York, NY: Pfizer; April 2004.

12. Lader M, Scotto JC. A multicentre double-blind comparison of hydroxyzine, buspirone and placebo in patients with generalized anxiety disorder. Psychopharmacology (Berl). 1998;139:402-406.

13. Fujii Y, Nakayama M. Effects of dexamethasone in preventing postoperative emetic symptoms after total knee replacement surgery: a prospective, randomized, double-blind, vehicle-controlled trial in adult Japanese patients. Clin Ther.?2005;27:740-745.

14. Carleton SC, Shesser RF, Pietrzak MP, et al. Double-blind, multicenter trial to compare the efficacy of intramuscular dihydroergot?amine plus hydroxyzine versus intramuscular meperidine plus hydroxyzine for the emergency department treatment of acute migraine headache. Ann Emerg Med. 1998;32:129-138.

15. Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol.?1997;78:157-159.

16. Einarson A, Bailey B, Jung G, et al. Prospective controlled study of hydroxyzine and cetirizine in pregnancy. Ann Allergy Asthma Immunol.?1997;78:183-186.

17. O?Donnell JF. Insomnia in cancer patients. Clin Cornerstone. 2004; 6(suppl 1D):S6-S14.

18. Lemoine P, Touchon J, Billardon M. Comparison of 6 different methods for lorazepam withdrawal. A controlled study, hydroxyzine versus placebo [in French]. Encephale. 1997;23:290-299.

19. Department of Health and Human Services. Overview of findings from the 2003 national survey on drug use and health. Available at www.oas.samhsa.gov/nhsda/2k3nsduh/2k3Overview.htm

20. Johnston LD, O?Malley PM, Bachman JG, et al. Monitoring the Future National Survey Results On Drug Use, 1975-2004. Volume I: Secondary School Students. Bethesda, Md: National Institute on Drug Abuse; 2005. NIH publication 05-5727. Available at http://monitoring thefuture.org/pubs.html.

21. Woody GE. Research findings on psychotherapy of addictive disorders. Am J Addict. 2003;12(suppl 2):S19-S26.

Answers: 1. A; 2. C; 3. D; 4. A; 5. A.



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