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Home , Acetylcysteine, Reboxetine

Dana Bartlett, RN, BSN, MSN, MA, CSPI

Dana Bartlett is a professional nurse and author. His clinical experience includes 16 years of ICU and ER experience and over 20 years of as a poison control center information specialist. Dana has published numerous CE and journal articles, written NCLEX material, written textbook chapters, and done editing and reviewing for publishers such as Elsevier, Lippincott, and Thieme. He has written widely on the subject of toxicology and was a contributing editor, toxicology section, for Critical Care Nurse journal. He is currently employed at the Rocky Mountain Poison Control Center.

ABSTRACT

Phencyclidine (PCP) is a dissociative anesthetic. Animal and human studies showed that PCP was an effective anesthetic and analgesic. There are multiple mechanisms of action of PCP that are responsible for its clinical effects. Phencyclidine mainly works as an NMDA . Phencyclidine can also inhibit the reuptake of the biogenic amines , , and . Phencyclidine causes significant adverse effects, delirium, depersonalization, dysphoria and hallucinations. As a consequence, PCP is no longer used in humans as an anesthetic. Phencyclidine continues to be used as an illicit drug. Although PCP is far less popular now than it was, its use continues. Phencyclidine intoxication can lead to PCP substance use disorder and it can cause serious, long-lasting morbidities.

1 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Policy Statement

This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 2.5 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity. Pharmacology content is 2.5 hours.

Statement of Learning Need

Phencyclidine causes significant adverse effects, and phencyclidine intoxication can lead to PCP substance use disorder and it can cause serious, long-lasting morbidities. Clinicians need to know how to identify PCP substance use disorder, and how to treat PCP intoxication.

Course Purpose

To inform health clinicians of PCP substance use disorder, and how to treat PCP intoxication.

2 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Target Audience

Advanced Practice Registered Nurses and Registered Nurses (Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Dana Bartlett, RN, BSN, MSN, MA, CSPI, William S. Cook, PhD, Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC – All have no disclosures.

Acknowledgement of Commercial Support

There is no commercial support for this course.

Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.

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1. Phencyclidine is a/an ______that has hallucinogenic and properties.

a. dissociative anesthetic b. anticonvulsant c. barbitutuate d. opiate

2. Phencyclidine mainly works as an NMDA receptor antagonist, a type of ______receptor.

a. histamine b. adrenergic c. glutamate d. GABA

3. Phencyclidine is primarily metabolized and excreted by the

a. kidneys. b. . c. . d. spleen.

4. ______is defined as a prolonged period of fixed, rigid posture.

a. Myoclonus b. Catalepsy c. Ataxia d. Catatonia

5. Phencyclidine is highly lipophilic, so it

a. is primarily excreted by the kidneys. b. requires active transport in order to cross the blood-brain barrier. c. cannot be smoked but must be ingested. d. easily crosses the blood-brain barrier.

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Introduction

Phencyclidine (PCP) is a dissociative anesthetic that was discovered in the 1920s and first used clinically in the late 1950s. It is marketed by the trade name Sernyl. Animal and human studies showed that PCP was an effective anesthetic and analgesic but it caused significant adverse effects, such as delirium, depersonalization, dysphoria and hallucinations. Because of the adverse effects, the application of PCP as an anesthetic for humans was quickly abandoned. By 1967, its use was officially restricted to animals. The illicit use of PCP, however, followed soon after. Although PCP is far less popular now than previously, the use of the drug continues, and PCP intoxication can lead to substance use disorder and cause serious and long- lasting morbidities.

Pharmacological Profile

Phencyclidine is a dissociative anesthetic that also has hallucinogenic and stimulant properties. An anesthetic prevents the patient from feeling pain and a dissociative drug produces a state of dissociation; the patient is awake but is not aware of and cannot respond to environmental stimulation. Phencyclidine is no longer used as an anesthetic in humans. It is categorized by the Drug enforcement Agency (DEA) to be a Schedule II drug, and considered dangerous with a high potential for a severe substance use disorder.

N-methyl-D-aspartate (NMDA) Receptor Antagonist

There are multiple mechanisms of action of PCP that are responsible for its clinical effects.1-3 Phencyclidine mainly works as an NMDA receptor antagonist. An NMDA receptor is a type of . Glutamate is the primary excitatory of the central nervous system

5 nursece4less.com nursece4less.com nursece4less.com nursece4less.com (CNS), and activation of the NMDA receptor causes inward movement of calcium and sodium ions and depolarization of the neuron. As an antagonist of an NMDA receptor, PCP would then have an inhibitory effect on the CNS. Paradoxically, PCP can also increase the release of glutamate, which may explain in part the intense excitation seen in PCP intoxication.

Biogenic Amine Reuptake Phencyclidine can inhibit the reuptake of the biogenic amines dopamine, norepinephrine, and serotonin.

Binding to the Sigma Receptor

The sigma receptor is a protein that is found in the membranes of neurons in certain parts of the central nervous system. Its function is not completely understood but ligand binding to the sigma receptor allows for ion movement, e.g., calcium and potassium, across cell membranes. It is thought that binding of PCP to sigma receptors is responsible for some of the behavioral, motor, physical, and psychological effects that are characteristic of PCP intoxication.1

Phencyclidine is usually found in powder form but PCP liquid and tablets are also manufactured. It is most often smoked by mixing the liquid or the powder with marijuana or but PCP is also ingested, injected, or insufflated (snorted). The drug is highly lipophilic, so it easily crosses the blood-brain barrier. The onset of effects depends on the route of administration (IV and smoking being the fastest), and the duration of intoxication is quite variable, ranging from ~ three hours to several days.1,4

Phencyclidine is primarily metabolized and excreted by the liver but a small amount is excreted by the kidneys, and this latter fact has some implications

6 nursece4less.com nursece4less.com nursece4less.com nursece4less.com for the detection and diagnosis of PCP intoxication. (Note: this topic will be discussed later in the module.)

Epidemiology

Accurate statistics on PCP use are not available. It is commonly stated that the popularity of PCP has decreased considerably since its peak in the 1970s,1 and a review of the medical database PubMed would seem to confirm this: using the search terms PCP overdose, PCP intoxication, phencyclidine intoxication, and phencyclidine overdose the first reports of PCP overdose were published in 1975 and the last (a review article) in 1990.

There are countless numbers of drug overdoses and intoxications that are not written about or reported, and the most current statistics this author located indicate that although PCP has been much less popular as a drug of abuse than , , prescription , or marijuana, the numbers are not insignificant. A study published in 2013 using information gathered by the Drug Abuse Warning Network (DAWN) noted that the estimated number of PCP-related visits to emergency departments (EDs) from 2005 to 2011 had increased 400%, from 14,825 to 75,538,5 and the National Survey on Drug Use and Health found that 2.4% of Americans 12 years of age or older had used PCP at least once.6 In contrast, the Centers for Disease Control and Prevention (CDC) reported that from July 2016 to September 2017, there were 142, 557 ED visits related to suspected overdose.6 Common names for PCP are angel dust, hog, horse tranquilizer, and elephant.

Phencyclidine Intoxication

The clinical presentation of PCP intoxication is quite variable. The most pronounced and dramatic signs of PCP intoxication are neurologic: confusion,

7 nursece4less.com nursece4less.com nursece4less.com nursece4less.com delirium, inattention to environmental stimulation, inability to respond to environmental cues, and violent behavior. In addition, significant psychological disturbances were noticed very soon after the initial use of PCP as anesthetic. In 1959, one researcher wrote that patients given PCP showed behavior that was remarkably like the primary symptoms of ,10 and these effects are explained by the pharmacologic actions of PCP. The signs, symptoms, and complications of PCP intoxication are listed in the following table.1,4,8,9

Signs, Symptoms, Complications of PCP Intoxication Agitation Analgesia Apnea Catatonia Catalepsy Cardiac arrest Coma Delirium Diaphoresis DIC Drowsiness Dystonic reactions Elevated Hallucinations Hypersalivation transaminases Hypertension Hyperthermia Hypoglycemia Muscle rigidity Nystagmus Psychosis Renal failure Rhabdomyolysis Seizures Tachycardia Violent behavior

Anesthetic Properties

Anesthetics prevent people from feeling pain and because of the diminished ability to feel pain during PCP intoxication, the patient can easily cause self- harm. The anesthetic effect of PCP may also explain why PCP causes catatonia and catalepsy. Catatonia is an extreme level of under- or over- activity of muscle tone and activity. Catalepsy is defined as a prolonged period of fixed, rigid posture, and both these conditions can be seen during PCP intoxication.

Dissociative Symptoms

Dissociation can be simply defined as separation. Phencyclidine causes an emotional, perceptual, and psychological detachment or separation of the

8 nursece4less.com nursece4less.com nursece4less.com nursece4less.com user the surrounding environment. Someone who is intoxicated with PCP is conscious but unable to perceive and cannot respond to the surrounding environment. In addition, the dissociatives cause amnesia and catalepsy, described above as a prolonged period of fixed, rigid posture.

Hallucinogenic Symptoms

A hallucinogen causes sensory and perceptual distortions. People who have taken a hallucinogen will see, hear and experience things that seem real but are not caused by an actual environmental stimulus or event. They can have emotions and thoughts that are (seemingly) not connected to the surroundings.

As previously mentioned, the duration of effects can be relatively brief, or they can be prolonged, and a comatose state lasting for seven days has been reported.1 The experience of PCP intoxication can be intense and the adverse effects very distressing. One of the researchers who had been involved in the human use of PCP in the 1950s and ‘60s later wrote: “It was astounding to us that phencyclidine became a major street drug of abuse. It was called PCP. Few of our volunteer subjects were ever willing to take the drug a second time. One former resident still recalls her PCP experience as intensely psychologically painful.”11

Intoxication Treatment

There is no for PCP intoxication. The treatment is standard, supportive care. Gastric decontamination would seldom be useful but a single dose of activated charcoal can be given, if this would be appropriate to the situation. Close attention should be paid to patient and staff safety, and to the patient’s temperature, pulse, and . Benzodiazepines are the preferred drug to treat the signs and symptoms of

9 nursece4less.com nursece4less.com nursece4less.com nursece4less.com PCP overdose and if benzodiazepine are not effective, or can be used.1 There has been concern that these drugs could be harmful in the context of PCP intoxication because they may decrease the seizure threshold and decrease the patient’s ability to dissipate heat; a review by Heard and Hoppe (2018) concluded that there is no high-quality evidence supporting this.1

Hypertension and tachycardia may be a symptom or complication of PCP intoxication; however, hypertension and tachycardia are usually brief in duration and should respond to sedation. If a clinician feels that blood pressure control is needed, a short-acting agent like nitroglycerin should be used.1

Hyperthermia can be treated with standard therapies like fluids and external cooling.1 Patients who are hypertensive, hyperthermic, extremely agitated, or who had a seizure or severe signs and symptoms, should be evaluated and monitored for the complications of disseminated intravascular coagulation (DIC), liver damage, and rhabdomyolysis.

After recovery from the physical effects of PCP intoxication some patients may develop a psychosis, and this may last for a day or two or several weeks,1,12,13 so psychiatric follow-up care should be considered. It is not clear if this is a drug-induced effect or it represents the effect of PCP on a patient who has an underlying psychiatric disorder, or both. Phencyclidine has also been associated with hallucinogen persisting perception disorder (HPPD).14,15

Hallucinogen persisting perception disorder is a rare phenomenon, usually caused by the hallucinogen LSD (lysergic acid diethylamide), that is

10 nursece4less.com nursece4less.com nursece4less.com nursece4less.com characterized by “... total or partial recurrence of perceptual disturbances that appeared during previous hallucinogenic “trips” or intoxications and re- emerged without recent use.”14 The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) criteria for HPPD are:16

After cessation of use of a hallucinogen, the patient re-experiences one or more of these perceptual symptoms that he or she had experienced while intoxicated with the hallucinogen, for example, hallucinations, halos around objects, false perceptions of movement in the peripheral visual fields, flashes of color, intensified colors, trial images of moving objects, positive after images, halos around objects, macropsia, and micropsia (objects in a person’s visual field appear larger [macropsia] or smaller [micropsia] than they actually are); the symptoms cause significant distress or impairment in social, occupational, or other important areas of functioning, and the symptoms are not due to a medical condition or explained by a mental disorder.

The onset of HPPD can be days or months after the last use of a hallucinogen and the symptoms may persist for years. Two types of HPPD are recognized, HPPD 1 and HPP2. Hallucinogen persisting perception disorder type 1 is relatively mild and some people who have HPPD 1 do not even seek treatment. Hallucinogen persisting perception disorder type 2 is more persistent, the symptoms are more severe and unlike HPPD 1, the patient’s condition and ability to function may slowly get worse.14 There is no information that can be used to identify people who are likely to develop HPPD. The incidence of HPPD caused by PCP is not known and there are very few documented cases; the incidence of HPPD associated with hallucinogen use has been estimated to be 4.2%.16

11 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Long-term effects of PCP have not been well-studied and little is known about the topic.17 Chronic use of PCP can cause tolerance and users may develop a substance use disorder.17 Other effects of long-term PCP use that have been reported are anxiety, depression, memory loss, social withdrawal, speech difficulties, and suicidal ideation, and these may persist long after the patient has stopped using PCP.17

There is little information about the effects on the fetus of PCP use during pregnancy, and no recent (prior five years) published information was located. The limited available data suggests that PCP use during pregnancy does not have long-term effects on a child but children born to mothers who used PCP have been noted to show signs of PCP intoxication and growth retardation and to require prolonged hospitalization.18-20

There is no information about the effects on nursing infants of maternal PCP use.22 Phencyclidine has been detected in breast milk (one reported case).21

Substance Use Disorder

A substance use disorder is defined by specific diagnostic criteria, categorized as mild, moderate, or severe, and characterized by recurrent use of or a drug, use that results in impaired functioning, health problems, and adverse personal, occupational, and social consequences. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, (DSM-5) uses 11 criteria to define substance use disorder.

A diagnosis of substance use disorder can be established if two or more of the 11 DSM-5 criteria are present within the 12 months prior to a patient’s assessment for substance use disorder.16 These criteria can be helpfully divided into four groups:

12 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1. Criteria 1-4: Impaired control 2. Criteria 5-7: Social impairment 3. Criteria 8-9: Risky use 4. Criteria 10-11: Pharmacological criteria

DSM-5 Criterion for Substance Use Disorder

The DSM-5 Criterion for a substance use disorder are listed as follows, including a brief discussion on the assessment of a person’s pattern of use.

1. Consuming more alcohol, or other substance, than was originally planned 2. Concern about stopping or having consistently failed efforts to control or stop use 3. Spending a large amount of time using drugs/alcohol, or in activities needed to obtain them 4. The person with a substance use disorder has a craving for alcohol or the drug. (Craving in the context of substance use disorder is a complex phenomenon but it is essentially a strong desire to use alcohol and/or a drug and often the inability to resist the desire.) 5. Substance use causes failure to meet significant obligations at home, school, and/or work 6. Continuing to use a substance despite mental or physical health problems caused or worsened by its use 7. Continuing the use of a substance despite its having negative effects on relationships with others 8. Repeated use of the substance in dangerous situation, for example, driving a car 9. Giving preference to alcohol or substance use over other life activities

13 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 10. Developing to a tolerance to the alcohol or drug. Tolerance is defined by the DSM-5 as needing to use noticeably larger amounts over time to get the desired effect or experiencing a diminished effect over time from the same amount 11. Withdrawal symptoms after stopping use

Mild substance use disorder is present if the patient has two or three symptoms or criteria listed in the 11 DSM-5 criteria for substance use disorder. Moderate substance use disorder is present if the patient has four to five symptoms. Severe substance use disorder is present if the patient has six or more symptoms. A substance use disorder in simple terms then is “substance use that is unregulated and destructive ... and progressively uncontrollable drug use in the face of negative consequences.”22

The initial assessment of a patient who is thought to have a substance use disorder should include a thorough history of the patient’s pattern of use. When conducting a thorough history. a clinician will ask the patient: What substances are currently being used? How much and how often is each substance used? When was the substance used last? What substances has the patient used in the past? How has the pattern of use affected the patient’s life?

The assessment should also include a thorough medical examination, a physical examination, and appropriate laboratory and/or diagnostic tests. A psychiatric assessment is very important to determine the presence of psychiatric disorders that would make treatment difficult or complicated and to assess the patient’s emotional and psychological ability to understand the problem and to participate in treatment.23

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The American Psychiatric Association DSM-5 categorizes PCP use disorder as one of the hallucinogenic-related disorders. The DSM-5 diagnostic criterion for PCP use disorder are listed here:16

1. Phencyclidine is taken in larger amount or over a longer period than the user originally intended. 2. The user has a persistent desire to control or cut down PCP use or has made unsuccessful attempts to do so. 3. The user spends a large amount of time obtaining PCP, using PCP, and recovering from PCP intoxication. 3. Craving or a strong desire to use PCP is present. 4. Persistent, recurrent PCP use has caused the user to fail to meet major obligation, socially, personally, and professionally at home, at work, and in the community. 5. There is continued, persistent use of PCP despite ongoing and significant problems caused by PCP; for example, loss of a job, legal consequences, financial difficulties, and damage to interpersonal relationships. 6. Phencyclidine use is preferred to and substituted for occupational, social, and recreational activities. 7. Phencyclidine is used during activities in which its use and intoxication is dangerous; for example, someone who uses PPC while operating a motor vehicle. 8. Phencyclidine use continues despite knowledge and understanding that its use is causing physical and psychological harm. 9. Tolerance, defined as: a) a need to markedly increase the amount of PCP needed to become intoxicated or to produce the desired effect; and, b) a markedly diminished effect when the same amount of PCP is used over time.

15 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 10. Withdrawal: The DSM-5 states that withdrawal signs and symptoms for the have not been established and although PCP withdrawal has been observed in animal studies, it has not been documented in humans.

As with other substance use disorders, a PCP use disorder is categorized as mild, moderate or severe based on the number of criteria that are present. In addition, the clinician should specify if the patient is in early remission or sustained remission and whether the patient is in a controlled environment.16

Early Remission:

None of the criteria for PCP use disorder have been present for at least three months, but some of them have been present in the previous 12 months except for the fourth criteria, craving.

Sustained Remission:

None of the criteria have been present in the previous 12 months or longer except for the fourth criteria, craving.

Controlled Environment:

The individual does not have access to PCP.

Basic Principles of Treatment

A short discussion of basic principles of substance use disorder treatment will be presented, followed by a summary of the available information on treatment specific to the PCP user. Treatment essentially begins with establishing the diagnosis of substance use disorder, assigning a level of

16 nursece4less.com nursece4less.com nursece4less.com nursece4less.com severity of the disorder, and determining the patient’s potential for and readiness to accept treatment. When these goals have been met, the clinician can use the data gleaned from this process as the basis for deciding what level of care is most appropriate. The American Society of has developed a detailed outline for this initial assessment process.24 This assessment process includes the following points.

Acute intoxication or the need for withdrawal:

Is the patient acutely intoxicated, or does the patient need medically managed withdrawal?

Biomedical:

Does the patient have any biomedical conditions that would affect substance abuse treatment? Is the patient pregnant? Does the patient have any communicable disease that could be transmitted to other patients or staff?

Behavioral, cognitive, psychological:

Does the patient have any mental disorders that would complicate treatment, that require stabilization and/or treatment (), or would make treatment risky? Is there readiness to change?

Relapse:

What is the patient’s risk for relapse?

Environment:

Is the patient’s environment conducive to or potentially detrimental to recovery? Environment may include family situation, financial resources, housing, and childcare issues.

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Readiness to Change: How Is It Determined?

Readiness to change is vital to the success of substance use disorder treatment and knowing the patient’s readiness is important for clinicians, but the term is not specific. The Stages of Change, Readiness, and Treatment Eagerness Scale (SOCRATES-8) is a 19-item assessment tool that was originally used when treating patients who have an alcohol use disorder. However, SOCRATES-8 does assess three elements that are important for any patient who has a substance use disorder and knowing these can help clinicians assess the patient’s readiness to change: recognition, ambivalence, and steps being taken to stop substance use.

An example would be asking the patient if these statements apply to his or her condition and the response would be scored as:

● “Sometimes I wonder if I am an alcoholic.”

● “If I don't change my drinking soon, my problems are going to get worse.”

● “I am actively doing things now to cut down or stop drinking.”

This assessment addresses two of the basic principles of successful substance use disorder treatment: 1) no single treatment is appropriate for, or will be successful for everyone, and 2) effective treatment must recognize that the patient has multiple needs that do not begin and end with just the patient and the patient’s substance use.25

The findings from the assessment will determine the level of care. Assuming the patient is not acutely intoxicated, there are two basic options: in-patient and patient.

18 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Outpatient care would be appropriate for patients who are not medically unstable, who do not need intensive medical treatment for withdrawal from another substance, who do not have psychiatric disorders that would require in-patient treatment, and who are in a safe environment. There are a wide variety of outpatient treatments and settings, and they vary primarily in their level of complexity and intensity. An intensive program involves a considerable patient and staff commitment of time. Intensive programs are highly scheduled, and multiple resources are needed. This type of program is suitable for patients whose readiness to change is not strong, whose potential for relapse is high, who have previous, unsuccessful attempts at treatment, and who require close monitoring and frequent contacts from the staff, as well as medical and/or psychiatric care and follow-up.

Inpatient care for a patient who has a substance use disorder has typically been used when the patient needs medically supervised withdrawal treatment or there are co-existing medical or psychiatric disorder that cannot be managed on an outpatient basis.

Co-occurrence of a Mental Disorder

The occurrence of a mental disorder in patients who have a substance use disorder is not unusual. Some studies estimate a lifetime prevalence of up to 90% for the occurrence of a mental disorder.26 Anxiety, mood disorders and bipolar disorder are common in this patient population.26-29 The co- occurrence of a mental disorder and a substance use disorder has been associated with poor treatment outcomes, more frequent relapse, and a poorer prognosis.26,28

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Unfortunately for many people, a substance use disorder is a long-term, chronic problem that can persist for many years.30 Relapse rates are very high, up to 60% within one year of treatment,31 and Dong, et al. (2017) stated that “High rates of relapse to drug use during abstinence is a defining feature of human drug addiction.”32

Given the prolonged course of a substance use disorder, typical, effective treatment needs to reflect the need for continued care. Continued care for a substance use disorder borrows concepts from the chronic care model of managing diseases. This approach considers substance use disorder a chronic problem that has genetic, environmental, physiological, and psychological components, and that requires commitment of time and resources. Primary goals of this model include those outlined below.30

● Consistent contact between the patient and clinicians.

● Goals: Defining and setting short-term and long-term goals, and clearly outlining what it means to reach those goals.

● Monitoring: Monitoring the patient’s progress is closely tied to the goals of treatment. Monitoring can be done in many ways, and monitoring techniques can be combined, added, or deleted as the situation warrants.

● : As relapses are frequent, clinicians should know what may trigger a relapse for a patient. Common precipitating factors may include co- occurring psychiatric problems, no or poor support structure, prior

20 nursece4less.com nursece4less.com nursece4less.com nursece4less.com relapses, high stress levels, and poor mechanism for coping with stress.

● Flexibility: The treatment for a patient who has a substance use disorder will need to change, in modality, intensity, and frequency.

● Resource Utilization: The patient who has a substance use disorder is usually part of a family and a community, and these social groups are an important resource and source of support.

● Treatment Approaches: The patient’s needs will determine what treatment approaches should be used.

● Self-management Skills: There are many self-management skills that can be helpful for a patient who has a substance use disorder. These include identifying obstacles that prevent abstinence, setting clear, attainable goals, and learning how to identify and cope with stressors that may precipitate a relapse. Primarily, the purpose of self-management skills is for patients to understand their substance use disorder, what can cause them to use, why treatment is being utilized (the goals), how to cope with stress, and what the available resources are and how to use them. Self-management skills basically help a patient know what the issue is and how best to treat it.

Treatment of Phencyclidine Use Disorder

The information about treatment of PCP use disorder is very limited. There were no articles on treating PCP use disorder found in Google Scholar and only five articles were located in the PubMed database, the last one published was in 1993.33-37 These studies were all small, they examined

21 nursece4less.com nursece4less.com nursece4less.com nursece4less.com heterogeneous patient populations, and the patients were or had been using other illicit intoxicants so given these limitations, no conclusions regarding treatment for PCP use disorder can be made.

It is not known what specific would be useful for treating a patient who was attempting to discontinue PCP use. Unlike the opioids or the benzodiazepines, there are no neuroreceptor antagonists that could be used and PCP withdrawal is not a described clinical condition. Pharmacologic treatment for HPPD has included anticonvulsants, atypical , benzodiazepines, , , , and the selective norepinephrine reboxetine (not sold in the US).38 These treatments have all been applied in small studies, many of them were non- controlled, and while there have been successes and failures, the data is remains limited and inconclusive.

Case Study

The following case study was obtained through a PubMed search to highlight a case of multiorgan failure with phencyclidine (PCP) use.39

A 42 year old woman was admitted in a worrisome state to the hospital emergency department (ED) with symptoms of confusion and severe bradycardia (20 beats per minute). Her prior medical history was unremarkable, and she was noted to be of Russian descent and divorced with two children. The outcomes in this case was documented by a medical team as being the first known case of PCP intoxication in (2005) with reference made to an alarming rise in prevalence rates within the .39

22 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Collateral information obtained from the patient’s boyfriend revealed she had attended a social party with him approximately 30 hours earlier and consumed vodka, 300 ml. She reportedly drank vodka to the point of passing out for 24 hours or longer and she continued to not awaken after being brought to the ED. Medications taken in the past were non-steroidal anti-inflammatory drugs (NSAIDS) and serotonin-selective reuptake inhibitors (SSRIs), and her boyfriend reported no current prescribed medication and denied illicit drug use or other non-prescription medication.

The patient was physically evaluated as well nourished and without evidence of trauma or unusual needle marks to her body. Cognitively, she was evaluated as disoriented with partial responsiveness to verbal stimuli. The vital signs were documented as: temperature was normal (36.7°C rectal), pulse 20 beats/min, strong and palpable at the radial, femora and carotid arteries, and respirations showed no dyspnea. Because of severe bradycardia, the blood pressure was unobtainable.

Neurologically, the patient’s pupils were dilated and partially responsive to light, with circular nystagmus. The rest of the physical examination was remarkable with the exception of vaginal bleeding. Laboratory testing revealed a blood glucose of 40 mg/dl. Blood chemistry, blood gases, prothrombin time, urine culture and toxicology screen were obtained. An electrocardiogram showed complexes with wide QRS and peaked T-waves, without P-waves.

Initial treatment included insertion of two intravenous (IV) lines and a urinary catheter with 50 ml of clear but concentrated urine returned. An immediate IV bolus of glucose 50%, 50 ml followed by glucose 10% was given with no response. The ECG showing continued bradycardia along with

23 nursece4less.com nursece4less.com nursece4less.com nursece4less.com olyguria indicated possible hyperkalemia and IV , adrenalin, and bicarbonate were emergently given along with IV glucose + insulin. She was also administered ventolin inhalations.

The patient stabilized hemodynamically (140 beats/min with blood pressure 130/70) within 10 minutes of treatment onset but hypoglycemia persisted. She awakened for a few minutes but resumed a state of partial consciousness.

The laboratory blood gas report indicated severe metabolic and respiratory acidosis: pH of 6.94 (normal 7.35–7.45), HCO3 10.6 mEq/L (normal 22–26 mEq/L), pCO2 76.2 mmHg (normal 35–45 mmHg), pO2 76.8 mmHg (normal 80–90 mmHg) and base excess 18.9 mEq/L (normal -2–2 mEq/L). Chemistry showed severe hyperkalemia 9.35 mEq/L (normal 3.5–5.1 mEq/L), hypoglycemia 17 mg/dl (normal 70–110 mg/dl), hyperuricemia 18.2 mg/dl (normal 2.4–7 mg/dl), acute renal failure with creatinine 4.06 mg/dl (normal 0.5–0.9 mg/dl), creatine phosphokinase above 5,000U/L (normal 24–195 U/L) and markedly elevated liver enzymes.

Complete blood count (CBC) showed hemoglobin 13.8 g/dl (normal 12–16 g/dl), white blood count 14,900 ml (normal 4,800–10,800) and platelets 209,000 ml (normal 130,000– 400,000). Blood cultures and viral serology for Epstein-Barr virus, cytomegalovirus, C virus, hepatitis B virus, herpes and human immunodeficiency virus showed that she was positive for hepatitis C virus (HCV) and other serology findings were negative. The International normalized ratio (INR) measured 2.9 (normal 0.9–1.3). Clotting factor V levels were 4% (normal 50–150%).

24 nursece4less.com nursece4less.com nursece4less.com nursece4less.com The patient’s urine qualitative toxicology screening (Multi-Drug One Step Screen Panel, Acon Laboratories, San Diego, CA, USA) was positive for opiates and PCP and negative for alcohol, acetaminophen, benzodiazepines, , , cannabis, , cocaine and .

The patient went into cardiac arrest after being intubated and mechanically ventilated. Her pulse returned after multiple doses of atropine and during the cardiac resuscitation effort and she stabilized. Hemodialysis was urgently initiated and the patient was admitted to the intensive care unit (ICU). While in the ICU, IV N-acetylcysteine (given empirically) and broad-spectrum antibiotics were administered. Fresh frozen plasma (FFP) and red blood cells (RBCs) were administered, as well.

Brain computed tomography scan ruled out an intracranial hemorrhage. Daily hemofiltration and treatment with MARS (molecular adsorbents recirculation system) was undertaken. By day 2 of the patient’s ICU stay she was diagnosed with compartment syndrome of the right arm, necessitating fasciotomy. Later, fever developed reaching 39.5°C. On day 3, the patient succumbed to multi-organ failure and died.

Discussion

Phencyclidine is currently illegally manufactured in laboratories and sold as a party drug, known as angel dust, ozone, wack, and rocket fuel. Combined with marijuana, PCP undergoes the name “killer joint and crystal supergrass”, reflecting the volatile effects of PCP. The drug is readily soluble in water or alcohol and is typically snorted, smoked, ingested, or injected intravenously. PCP can be smoked by adding it to leafy material such as an herbal or marijuana product.

25 nursece4less.com nursece4less.com nursece4less.com nursece4less.com As mentioned in earlier sections, PCP intoxication has an extremely variable clinical presentation. In adult patients the clinical signs of PCP use and intoxication can be grouped; patterns include “coma, catatonic syndrome, toxic psychosis and acute brain syndrome. Coma may last from 2 to 24 hours, and the symptoms are more intense. Patients with severe toxicity, including status epilepticus and malignant hyperthermia, may remain in coma for 1 day to 3 weeks. These patients often have respiratory or metabolic acidosis and rhabdomyolysis”.39 At the time of this study of a case if PCP intoxication and death in Israel, there were more cases of PCP cases in the United States according to American Association of Poison Control Centers with the majority of mortality cases related to combined PCP and other drugs (for example, cocaine or benzodiazepines).

This case reported highlighted the fact that there has been a “steady increase in documented toxic exposure to PCP”.39 This was the first documented case of PCP exposure in Israel although it has been a common street drug in the U.S. The patient in this case study was diagnosed as having died from PCP-induced hyperthermia, resulting in severe liver failure and rhabdomyolysis that led into multiorgan failure of acute renal failure, hyperkalemia and acidosis. The patient was reported to remain unconscious during most of her hospital course of care. The positive urine drug screen for opiates likely contributed to the fatal outcome due to complications of known respiratory failure and cardiac complications exacerbated by opiate use.

False positive PCP screening results in patients treated with an SSRI, or , have been reported however in this case the family denied their use. The diagnosis of HCV-positive in this patient’s case was not viewed to be a contributing factor to acute hepatic failure as she was a stable HCV carrier.

26 nursece4less.com nursece4less.com nursece4less.com nursece4less.com It is well known that PCP is often mixed with other narcotics and recreational drugs. The authors highlighted in this case report that the “presence of acute circular nystagmus with dilated pupils, encephalopathy, and persistent hypoglycemia, rhabdomyolysis complicated by compartment syndrome, acute renal failure and liver necrosis in a previously healthy patient without evidence of alcohol, or cocaine consumption, is highly suspicious for PCP intoxication even without a positive toxic screen”.39 This case is evidence of the challenge clinicians are confronted by when treating severe PCP intoxication.

Summary

Phencyclidine (PCP) is a dissociative anesthetic, the illicit use of PCP has continued, and PCP intoxication can lead to serious and long-lasting morbidities and a substance use disorder. The exact incidence of PCP use is not known.

Phencyclidine is categorized by the Drug enforcement Agency (DEA) to be a Schedule II drug. It is considered dangerous and it has a high potential for a severe substance use disorder. Phencyclidine is a dissociative anesthetic that also has hallucinogenic and stimulant properties, and it is usually found in powder form, but PCP liquid and tablets are also manufactured. It is most often smoked by mixing the liquid or the powder with marijuana or tobacco, but PCP is also ingested, injected, or insufflated (snorted). The duration of drug intoxication can vary from three hours to several days. The most pronounced and dramatic signs of PCP intoxication are neurologic: confusion, delirium, inattention to environmental stimulation, inability to respond to environmental cues, and violent behavior. Other signs and symptoms include hypertension, hyperthermia, tachycardia and in severe cases, coma and seizures.

27 nursece4less.com nursece4less.com nursece4less.com nursece4less.com There is no antidote for PCP intoxication; the treatment is standard, supportive care. Recovery from the physical effects of PCP intoxication may result in residual effects such as psychosis of varying duration. Long-term effects of PCP have not been well studied and little is known about the topic. Although PCP use disorder is a DSM-5 diagnosis, more can be said about case outcomes and PCP treatment. There is no pharmacological treatment for PCP use disorder, and clinicians are rely upon basic principles of treatment for individuals with a substance use disorder.

Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the self-assessment of Knowledge Questions after reading the article, and providing feedback in the online course evaluation.

Completing the study questions is optional and is NOT a course requirement.

28 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1. Phencyclidine is a/an ______that has hallucinogenic and stimulant properties.

a. dissociative anesthetic b. anticonvulsant c. barbitutuate d. opiate

2. Phencyclidine mainly works as an NMDA receptor antagonist, a type of ______receptor.

a. histamine b. adrenergic c. glutamate d. GABA

3. Phencyclidine is primarily metabolized and excreted by the

a. kidneys. b. liver. c. lungs. d. spleen.

4. ______is defined as a prolonged period of fixed, rigid posture.

a. Myoclonus b. Catalepsy c. Ataxia d. Catatonia

5. Phencyclidine is highly lipophilic, so it

a. is primarily excreted by the kidneys. b. requires active transport in order to cross the blood-brain barrier. c. cannot be smoked but must be ingested. d. easily crosses the blood-brain barrier.

6. True or False: Phencyclidine has an inhibitory effect on the central nervous system (CNS) by decreasing the release of glutamate but it also increases the release of glutamate causing an excitation of the CNS.

a. True

29 nursece4less.com nursece4less.com nursece4less.com nursece4less.com b. False 7. Phencyclidine causes an ______detachment or separation of the user from his or her environment.

a. emotional b. perceptual c. psychological d. All of the above

8. There is evidence that phencyclidine (PCP) intoxication in children born from mothers who use PCP

a. causes long-term effects. b. has no effect. c. may cause growth retardation. d. causes permanent perceptual detachment.

9. The preferred drug treatment for phencyclidine (PCP) overdose is

a. benzodiazepines. b. gastric decontamination. c. haloperidol. d. droperidol.

10. Following phencyclidine (PCP) intoxication, a clinician may feel that blood pressure control is needed, in which case the clinician should treat with

a. a benzodiazepine. b. haloperidol lactate. c. a short-acting agent like nitroglycerin. d. droperidol.

11. After recovery from the physical effects of PCP intoxication some patients may develop a psychosis, and this may last

a. indefinitely. b. up to several weeks. c. up to several hours. d. several months.

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12. Effects of long-term phencyclidine (PCP) use that may persist long after a patient stops using PCP have reportedly included

a. growth retardation. b. hyperthermia. c. rhabdomyolysis. d. memory loss.

13. Severe substance use disorder is present if the patient has ______symptoms or criteria listed in the 11 DSM-5 criteria for substance use disorder.

a. six or more b. any of the c. three or more d. four to five

14. The DSM-5 diagnostic criterion for phencyclidine (PCP) use disorder include tolerance, which is defined as

a. a user who was unsuccessful in reducing his or her PCP use. b. a need to markedly increase the amount of PCP needed to become intoxicated or to produce the desired effect. c. a user craving or having a strong desire to use PCP. d. a user who will not experience withdrawal symptoms if he or she stops using PCP.

15. Which of the following medications is useful for treating a patient who wants to stop using phencyclidine (PCP)?

a. There are no neuroreceptor antagonists that may be used to aid a patient to stop using PCP. b. Anticonvulsants may be used to aid a patient to stop using PCP. c. Naloxone is the first-line drug for PCP cessation. d. The selective norepinephrine re-uptake inhibitor reboxetine is used in the United States to treat PCP use disorder.

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CORRECT ANSWERS:

1. Phencyclidine is a/an ______that has hallucinogenic and stimulant properties.

a. dissociative anesthetic

“Phencyclidine is a dissociative anesthetic that also has hallucinogenic and stimulant properties.”

2. Phencyclidine mainly works as an NMDA receptor antagonist, a type of ______receptor.

c. glutamate

“Phencyclidine mainly works as an NMDA receptor antagonist. An NMDA receptor is a type of glutamate receptor.”

3. Phencyclidine is primarily metabolized and excreted by the

b. liver.

“Phencyclidine is primarily metabolized and excreted by the liver but a small amount is excreted by the kidneys, and this latter fact has some implications for the detection and diagnosis of PCP intoxication.”

4. ______is defined as a prolonged period of fixed, rigid posture.

b. Catalepsy

“The anesthetic effect of PCP may also explain why PCP causes catatonia and catalepsy. Catatonia is an extreme level of under- or over-activity of muscle tone and activity. Catalepsy is defined as a prolonged period of fixed, rigid posture, and both these conditions can be seen during PCP intoxication.”

5. Phencyclidine is highly lipophilic, so it

d. easily crosses the blood-brain barrier.

“Phencyclidine is usually found in powder form but PCP liquid and tablets are also manufactured. It is most often smoked by mixing the liquid or the

32 nursece4less.com nursece4less.com nursece4less.com nursece4less.com powder with marijuana or tobacco but PCP is also ingested, injected, or insufflated (snorted). The drug is highly lipophilic, so it easily crosses the blood-brain barrier.” 6. True or False: Phencyclidine has an inhibitory effect on the central nervous system (CNS) by decreasing the release of glutamate but it also increases the release of glutamate causing an excitation of the CNS.

a. True

“As an antagonist of antagonism at an NMDA receptor, PCP would then have an inhibitory effect on the CNS. Paradoxically, PCP can also increase the release of glutamate, which may explain in part the intense excitation seen in PCP intoxication.”

7. Phencyclidine causes an ______detachment or separation of the user from his or her environment.

a. emotional b. perceptual c. psychological d. All of the above [correct answer]

“Phencyclidine causes an emotional, perceptual, and psychological detachment or separation of the user from his or her environment.”

8. There is evidence that phencyclidine (PCP) intoxication in children born from mothers who use PCP

c. may cause growth retardation.

“The limited available data suggests that PCP use during pregnancy does not have long-term effects on a child but children born to mothers who used PCP have been noted to show signs of PCP intoxication and growth retardation and to require prolonged hospitalization.”

9. The preferred drug treatment for phencyclidine (PCP) overdose is

a. benzodiazepines.

“Gastric decontamination would seldom be useful but a single dose of activated charcoal can be given, if this would be appropriate to the situation.... Benzodiazepines are the preferred drug to treat the signs and

33 nursece4less.com nursece4less.com nursece4less.com nursece4less.com symptoms of PCP overdose and if benzodiazepine are not effective, haloperidol or droperidol can be used.”

10. Following phencyclidine (PCP) intoxication, a clinician may feel that blood pressure control is needed, in which case the clinician should treat with c. a short-acting agent like nitroglycerin.

“Hypertension and tachycardia may be a symptom or complication of PCP intoxication; however, hypertension and tachycardia are usually brief in duration and should respond to sedation. If a clinician feels that blood pressure control is needed, a short-acting agent like nitroglycerin should be used.”

11. After recovery from the physical effects of PCP intoxication some patients may develop a psychosis, and this may last b. up to several weeks.

“After recovery from the physical effects of PCP intoxication some patients may develop a psychosis, and this may last for a day or two or several weeks, so psychiatric follow-up care should be considered.”

12. Effects of long-term phencyclidine (PCP) use that may persist long after a patient stops using PCP have reportedly included d. memory loss.

“Long-term effects of PCP ... can cause tolerance and users may develop a substance use disorder. Other effects of long-term PCP use that have been reported are anxiety, depression, memory loss, social withdrawal, speech difficulties, and suicidal ideation, and these may persist long after the patient has stopped using PCP.”

13. Severe substance use disorder is present if the patient has ______symptoms or criteria listed in the 11 DSM-5 criteria for substance use disorder. a. six or more

“Mild substance abuse disorder is present if the patient has two or three symptoms or criteria listed in the 11 DSM-5 criteria for substance use disorder. Moderate substance abuse disorder is present if the patient has

34 nursece4less.com nursece4less.com nursece4less.com nursece4less.com four to five symptoms. Severe substance use disorder is present if the patient has six or more symptoms.”

14. The DSM-5 diagnostic criterion for phencyclidine (PCP) use disorder include tolerance, which is defined as b. a need to markedly increase the amount of PCP needed to become intoxicated or to produce the desired effect.

“The American Psychiatric Association DSM-5 categorizes PCP use disorder as one of the hallucinogenic-related disorders. The DSM-5 diagnostic criterion for PCP use disorder are listed here: … Tolerance, defined as: a) a need to markedly increase the amount of PCP needed to become intoxicated or to produce the desired effect; and, b) a markedly diminished effect when the same amount of PCP is used over time.”

15. Which of the following medications is useful for treating a patient who wants to stop using phencyclidine (PCP)? a. There are no neuroreceptor antagonists that may be used to aid a patient to stop using PCP.

“It is not known what specific medications would be useful for treating a patient who was attempting to discontinue PCP use. Unlike the opioids or the benzodiazepines, there are no neuroreceptor antagonists that could be used and PCP withdrawal is not a described clinical condition. Pharmacologic treatment for HPPD has included anticonvulsants, atypical antipsychotics, benzodiazepines, clonidine, naloxone, phenothiazines, and the selective norepinephrine re-uptake inhibitor reboxetine (not sold in the US). These treatments have all been applied in small studies, many of them were non- controlled, and while there have been successes and failures, the data is too sparse to use for practical conclusions.”

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Reference Section

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.

1. Heard K, Hoppe J. (2018). Phencyclidine (PCP) intoxication in adults. UpToDate. Retrieved from https://www.uptodate.com/contents/phencyclidine-pcp-intoxication-in- adults?search=phencyclidine&source=search_result&selectedTitle=1~62 &usage_type=default&display_rank=1. 2. Lodge D, Mercier MS. (2015). and phencyclidine: the good, the bad and the unexpected. Br J Pharmacol. 2015;172(17):4254-4276. 3. DeWeert D, Lovell E, Patel S. (2018). Computed tomography angiography-negative aortic dissection in a patient using phencyclidine. World J Emerg Med. 2018;9(2):144-148. 4. Armenian P. Phencyclidine (PCP) and ketamine. In: Olson KR, Anderson IB, Benowitz NL, Blanc PD, Clark RF, Kearney TE, Kim-Katz S, Wu AHB, eds. Poisoning & . 7th ed. New York, NY: McGraw-Hill Education. 2018;365-369. 5. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (2013). The DAWN Report: Emergency Department Visits Involving Phencyclidine (PCP). Rockville, MD. Retrieved from http://www.samhsa.gov/data/sites/default/files/DAWN143/DAWN143/sr 143-emergency-phencyclidine-2013.htm 6. National Institutes of Health. National Institute on Drug Abuse. National Survey on Drug Use and Health: Trends in Prevalence of Various Drugs for Ages 12 or Older, Ages 12 to 17, Ages 18 to 25, and Ages 26 or Older; 2015 - 2016 (in percent). Retrieved from https://www.drugabuse.gov/national-survey-drug-use-health. 7. Centers for Disease Control and Prevention. (2018). Vital Signs: Trends in Emergency Department Visits for Suspected Opioid Overdoses — United States, July 2016–September 2017. CDC. Retrieved from https://www.cdc.gov/mmwr/volumes/67/wr/mm6709e1.htm. 8. Bey T, Patel A. (2007). Phencyclidine intoxication and adverse effects: a clinical and pharmacological review of an illicit drug. Cal J Emerg Med. 2007;8(1):9-14.

36 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 9. McCarron MM, Schulze BW, Thompson GA, Conder MC, Goetz WA. (1981). Acute phencyclidine intoxication: incidence of clinical findings in 1,000 cases. Ann Emerg Med. 1981;10(5):237-242. 10. Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelly R. (1959). Study of a new schizophrenic-like drug: Sernyl. Arch Neurol Psychiat. 1959; 81:363–369 11. Domino EF, Luby ED. (2012). Phencyclidine/schizophrenia: one view toward the past, the other to the future. Schizophr Bull. 2012;38(5):914-919. 12. Carls KA, Ruehter VL. (2006). An evaluation of phencyclidine (PCP) psychosis: a retrospective analysis at a state facility. Am J Drug Alcohol Abuse. 2006;32(4):673-678. 13. Fauman B, Aldinger G, Fauman M, Rosen P. (1976). Psychiatric sequelae of phencyclidine abuse. Clin Toxicol. 1976;9(4):529-538. 14. Martinotti G, Santacroce R, Pettorruso M, et al. (2018). Hallucinogen persisting perception disorder: Etiology, clinical features, and therapeutic perspectives. Brain Sci. 2018 Mar 16;8(3). pii: E47. 15. Brodrick J, Mitchell BG. (2016). Hallucinogen persisting perception disorder and risk of suicide. J Pharm Pract. 2016;29(4):431-434. 16. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. APA. Washington, DC: American Psychiatric Publishing; 2013. 17. National Institutes of Health. National Institute on Drug Abuse. Hallucinogens and Dissociative Drugs. NIH. Retrieved from https://www.drugabuse.gov/publications/hallucinogens-dissociative- drugs/how-do-hallucinogens-lsd-psilocybin-peyote-dmt-ayahuasca- affect-brain-body. 18. Rahbar F Fomufod A, White D, Westney LS. (1993). Impact of intrauterine exposure to phencyclidine (PCP) and cocaine on neonates. J Natl Med Assoc. 1993;85(5):349-352. 19. Tabor BL, Smith-Wallace T, Yonekura ML. (1990). Perinatal outcome associated with PCP versus cocaine use. Am J Drug Alcohol Abuse. 1990;16(3-4):337-348. 20. Chasnoff IJ, Burns WJ, Hatcher RP, Burns KA. (1983). Phencyclidine: effects on the fetus and neonate. Dev Pharmacol Ther. 1983;6(6):404- 408. 21. U.S. National Library of Medicine. TOXNET. LactMed. Phencyclidine. Retrieved from https://www.toxnet.nlm.nih.gov/cgi-bin/sis/search2. 22. Elias D, Kleber HD. (2017). Minding the brain: the role of pharmacotherapy in substance-use disorder treatment. Dialogues Clin Neurosci. 2017;19(3):289-297. 23. Dugosh KL, Cacciola JS, (2017). Clinical assessment of substance use disorders. UpToDate. Retrieved from

37 nursece4less.com nursece4less.com nursece4less.com nursece4less.com https://www.uptodate.com/contents/clinical-assessment-of-substance- use-disorders?topicRef=313&source=see_link. 24. Hartwell K, Brady K. (2018). Determining appropriate levels of care for treatment of substance use disorders. UpToDate. January 30, 2018. Retrieved from https://www.uptodate.com/contents/determining- appropriate-levels-of-care-for-treatment-of-substance-use- disorders?search=treatment%20of%20substance%20use%20disorder& source=search_result&selectedTitle=1~150&usage_type=default&displa y_rank=1 25. National Institutes of Health. National Institute on Drug Abuse. (2018). Principles of Drug Addiction Treatment: A Research-Based Guide (3rd Ed.). Principles of Effective Treatment. NIH. Retrieved from https://www.drugabuse.gov/publications/principles-drug-addiction- treatment-research-based-guide-third-edition/principles-effective- treatment. 26. Dauber H, Braun B, Pfeiffer-Gerschel T, Kraus L, Pogarell O. (2018). Co- occurring mental disorders in substance abuse treatment: the current health care situation in . Int J Ment Health Addict. 2018;16(1):66-80. 27. Tolliver BK, Anton RF. (2015). Assessment and treatment of mood disorders in the context of substance abuse. Dialogues Clin Neurosci. 2015;17(2):181-190. 28. Gold AK, Otto MW, Deckersbach T, Sylvia LG, Nierenberg AA, Kinrys G. (2018). Substance use comorbidity in bipolar disorder: A qualitative review of treatment strategies and outcomes. Am J Addict. 2018;27(3):188-201. 29. Pettinati HM, O'Brien CP, Dundon WD. (2013). Current status of co- occurring mood and substance use disorders: a new therapeutic target. Am J Psychiatry. 2013;170(1):23-30. 30. McKay JR. (2017). Continuing care for addiction: Indications, features, and efficacy. UpToDate. Retrieved from https://www.uptodate.com/contents/continuing-care-for-addiction- indications-features-and-efficacy?topicRef=7799&source=see_link. 31. Thompson TP, Taylor AH, Wanner A, et al. (2018). Physical activity and the prevention, reduction, and treatment of alcohol and/or substance use across the lifespan (The PHASE review): protocol for a systematic review. Syst Rev. 2018 Jan 22;7(1):9. 32. Dong Y, Taylor JR, Wolf ME, Shaham Y. (2017). Circuit and synaptic plasticity mechanisms of drug relapse. J Neurosci. 2017;37(45):10867- 10876. 33. Giannini AJ, Loiselle RH, Graham BH, Folts DJ. (1993). Behavioral response to in cocaine and phencyclidine withdrawal. J Subst Abuse Treat. 1993;10(6):523-527.

38 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 34. Gorelick DA, Wilkins JN. (1989). Inpatient treatment of PCP abusers and users. Am J Drug Alcohol Abuse. 1989;15(1):1-12. 35. Gorelick DA, Wilkins JN, Wong C. (1989). Outpatient treatment of PCP abusers. Am J Drug Alcohol Abuse. 1989;15(4):367-374. 36. Giannini AJ, Malone DA, Giannini MC, Price WA, Loiselle RH. (1986). Treatment of depression in chronic cocaine and phencyclidine abuse with . J Clin Pharmacol. 1986;26(3):211-214. 37. De Angelis GG, Goldstein E. (1978). Treatment of adolescent phencyclidine (PCP) abusers. Am J Drug Alcohol Abuse. 1978;5(4):399- 414. 38. Orsolini L, Papanti GD, De Berardis D, et al. (2017). The "endless trip" among the NPS Users: Psychopathology and psychopharmacology in the hallucinogen-persisting perception disorder. A systematic review. Front Psychiatry. 2017 Nov 20;8:240. 39. Stein, G., et al. (2005). Phencyclidine-Induced Multi-Organ Failure. Case Communications. Department of Internal Medicine and Institute of Nephrology, Rabin Medical Center (Golda Hasharon Campus), Petah Tiqva, Israel General Intensive Care Unit, Rabin Medical Center (Beilinson Campus), Petah Tiqva, Israel Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel. IMAJ 2005;7:535– 537.

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