Withdrawal Are Important in the CSA 8-Factor Analysis to Inform Drug Scheduling Recommendations

Jack E. Henningﬁeld, Ph.D. Vice President, Research, Health Policy and Abuse Liability Pinney Associates And Professor, Adjunct, Behavioral Biology Department of Psychiatry and Behavioral Sciences The Johns Hopkins University School of Medicine Presented at ASAM, April 9, 2017, from 8:30-10:00 am at the Grand Salon A, In the Symposium: Evaluating Drug Dependence: Regulatory, Methodological and Clinical Challenges. New Orleans Hilton Riverside

1 PinneyAssociates.com

Through PinneyAssociates, I provide consulting services on the development and regulation of pharmaceutical products and electronic nicotine delivery systems for which development goals may include reduced abuse potential. This includes abuse potential assessment and abuse-deterrent drug formulation evaluation to inform scheduling and abuse-deterrent labeling recommendations.

2 PinneyAssociates.com Parallels with one of the 20th century’s top 10 public health advances: Cars made with better materials and designs, and safeguards to protect passengers, better education, and with regulatory standards and oversights that incentivizes advances by industry

3 PinneyAssociates.com 1. Developing medicines with lower risks of abuse and physical dependence – a shared goal of FDA, public health, and pharmaceutical companies

2. Goals and challenges for new medications development

3. Deﬁnitions and why they matter

4. Clinical trials: At the intersection of research and clinical practice: A critical but challenging opportunity to characterize the abuse and physical dependence potential of new medicines

5. The Controlled Substances Act (CSA) 8 Factors to guide drug scheduling recommendations by FDA, NIDA and DEA

4 PinneyAssociates.com 1. FDA incentivized pharma with the potential for less restrictive scheduling and abuse deterrent labeling for opioids – but it needs science to get it right

2. The roadmap oﬀered by the 2017 ﬁnal Guidance for Assessment of Abuse Potential of Drugs provides a path and a basis for decision making for scheduling

3. The 2015 Opioid Abuse Deterrent Guidance recommends research strategies to achieve potential abuse deterrent claims

4. Clinicians and researchers can have input and help keep FDA and pharma on the right path

5 PinneyAssociates.com 1. Better medicines may be important in reducing prescription abuse and overdose but this may drive some to illicit drugs. We also need:

2. Better education of the public and prescribers

3. Better balance of prevention and treatment eﬀorts to reduce demand along with supply reduction eﬀorts

4. Nationwide implementation of strategies advocated by ASAM & NIDA

5. As Dr. Koop said in his 90th birthday address: 1. Politics should serve public health and not the other way around 2. We need to make it as easy to get treatment as it is to get addicting drugs

6 PinneyAssociates.com 1. Physical dependence and withdrawal are important in the CSA 8-Factor Analysis to inform drug scheduling recommendations

2. Labeling must describe the nature and course of potential withdrawal symptoms and how they can be minimized and treated

3. Phase 3 trials provide the closest approximation to real world clinical use, with the chronic exposure that would be expected to produce dependence and lead to abuse and diversion – if those are risks of the drug

4. NDAs for CNS drugs must include an abuse potential assessment, including Phase 3 data, to inform the FDA’s scheduling recommendation to DEA

7 PinneyAssociates.com Serve Patients & Providers Deter Abuse & Overdose – primarily in nonpatients Patients want effective, fast acting, easy and flexible to use Those same features can be attractive to non-patients seeking mood alteration medicines (e.g., can crush and put in apple sauce) Formulations & effects intended to discourage abuse in non patients may Minimize risk of adverse effects & introduce new potential risks quality of life impairing effects It can take many years and great expense to develop and get approved a product that Support compliant use while may discourage abuse but offers little or no minimizing iatrogenic addiction benefit that patients or insurance (or, e.g., risk the VA) will pay for

8 PinneyAssociates.com “Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social and spiritual manifestations. This is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors. Addiction is characterized by inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death.” See complete ASAM definition for more detail

9 PinneyAssociates.com ! Patient: “Doctor, will this drug make me addicted? The label says it may cause dependence and withdrawal” ! Doctor: “The risk of dependence when used according to the labeling is low but your body will develop tolerance and may become physically dependent so we will need to taper you oﬀ it when you no longer need it to minimize your withdrawal” ! Patient: “Huh? You mean my body is addicted but I’m not? That doesn’t make sense. Are you a medical marijuana user?”

10 PinneyAssociates.com ! Drug abuse is defined as the intentional, non-therapeutic use of a drug product or substance, even once, to achieve a desired psychological or physiological effect. Therefore, abuse potential refers to the likelihood that abuse will occur with a particular drug product or substance with CNS activity. Desired psychological effects can include euphoria, hallucinations and other perceptual distortions, alterations in cognition, and changes in mood.

! Dependence refers to physical or psychological dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a signiﬁcant dose reduction of a drug. ! Psychological (or psychic) dependence refers to a state in which individuals have impaired control over drug use based on the rewarding properties of the drug (ability to produce positive sensations that increase the likelihood of drug use) or the psychological distress produced in the absence of the drug. Continued --

11 PinneyAssociates.com ! Tolerance is a state that develops as a result of physiological adaptation characterized by a reduced response to a specific dose of drug after repeated administration of the drug (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). ! The presence of physical dependence or tolerance does not determine whether a drug has abuse potential. Many medications that are not associated with abuse, such as antidepressants, betablockers, and centrally acting antihypertensive drugs, can produce physical dependence and/or tolerance after chronic use. ! However, if a drug has rewarding properties, the ability of that drug to induce physical dependence or tolerance may influence its overall abuse potential.

12 PinneyAssociates.com ! Assessment of abuse potential and potential to produce physical dependence and withdrawal were relatively simple largely based on small scale laboratory studies (e.g. animal drug self-administration & withdrawal) and human lab studies of abuse potential & withdrawal

! Most substances in development ﬁt reasonably neatly into one of few classes: namely opioids, stimulants and sedatives

! Phase 3 clinical trial data were not a major factor in scheduling decisions

13 PinneyAssociates.com ! They address new novel acting substances and products designed to reduce abuse/dependence can be more challenging to characterize in part due to weaker or novel eﬀects

! They guide study planning from bench & clinical trials to post- marketing for the overall abuse potential assessment portfolio with a menu of suggestions to be considered (and ideally discussed with FDA)

! They provide a path toward potential less restrictive scheduling and other labeling claims to incentivize pharmaceutical development

14 PinneyAssociates.com ! No single test or characteristic alone is predictive [for scheduling] ! Composite of multiple sources of data ! Evaluation of: " Chemistry " Pharmacology (animal and human) " Pharmacokinetics & pharmacodynamics " Adverse events reported in clinical trials ! Compare to a pharmacologically similar substance

(From FDA, Mike Klein, October 26, 2007 – See 2017 Guidance for “road map”)

15 PinneyAssociates.com ! Reliance on Phase 3 trial data was increasingly encouraged by FDA since about 2002 ( at CPDD/NIDA/ FDA conference – Special DAD Issue 2003) ! Phase 3 trials primarily designed for eﬃcacy and safety, not abuse and physical dependence potential ! Often lack balanced dose manipulations and appropriate comparator drugs that are important in abuse/withdrawal determinations ! Many drugs are intended to make patients feel better and feel good – but not “high” or “inappropriately euphoric” may provide confusing signals ! Study site staﬀ training and experience in such assessments varies

16 PinneyAssociates.com ! Yes! I can ﬁnally – " Sleep " Function " Deal with stress " Hug my kids " Dance ! How to distinguish from inappropriate euphoria?

! Similarly, are post drug emergent “ill eﬀects” the emergence of the underlying illness or a withdrawal syndrome caused by development of physical dependence on the drug or both can be challenging.

! Documentation of the time course of symptoms relative to drug treatment and following the FDA 2017 Guidance is critical

17 PinneyAssociates.com ! po

Potential strong mood swings may merit follow-up to help understand if mood is “inappropriate” or a result of desired clinical beneﬁts of the drug

18 PinneyAssociates.com Controlled Substances Act 8-Factors for Drug Scheduling Recommendations

7 4 Psychic and/ History or or 6 current physiological Public pattern of dependence 8 5 health risk abuse liability 3 Already Scope, Other Controlled duration, 2 scientiﬁc substance or signiﬁcance knowledge precursor of abuse Pharmacology 1 Actual and known potential for abuse

CV: Pregabalin, CIV: CIII CII: CI: Unscheduled Diazepam, Ketamine, Oxycodone, Low dose Heroin, LSD, Codeine Fospropofol Pentobarbital Amphetamine Marijuana combo

19 PinneyAssociates.com ! Consider carefully FDA’s 2017 guidance ﬁnal Assessment of Abuse Potential Guidance. For abuse-deterrent claims and evaluation of drug “chemistry” consult the 2015 Abuse Deterrent Opioids

! Use FDA terminology and be consistent from trial design to FDA ﬁling

! Use current state of the art and approaches accepted by FDA and/or modiﬁcations discussed with FDA

! Assessments in Phase 3 trials often require working within practical constraints of the trial and reliance on indirect measures such as spontaneous AE reports that might, but do not necessarily, reﬂect abuse, dependence or withdrawal – Discuss approach with FDA

20 PinneyAssociates.com ! As evidenced by the FDA’s 2017 final guidance on Assessment of Abuse Potential and 2015 final guidance on Abuse Deterrent Opioids, the science has evolved enormously in recent decades – BTW: FDA helped drive and guide many scientific advance

! The 2017 FDA Guidance provides a reasonably orderly path for evaluation, and labeling, including scheduling

! Advances in molecules and formulations are increasing giving us the opportunity to truly improve medicine and public health

21 PinneyAssociates.com

I am an employee of INC Research and in my role consult with various pharmaceutical and biotech companies • Key considerations for designing dependency trials: • Population type (healthy vs patient) • Trial type (phase I vs II/III) • Study design (double-blind, open label) • Duration of exposure • Duration of withdrawal follow up • Types of measurements • Frequency of assessments

• Patient populations are best suited when: • The investigational drug can be safely withdrawn without conversion to other therapy • Patient pathology is not a confounder with withdrawal symptoms

• Trial type depends on population • Healthy volunteers – Phase I • Patient Population – Phase II/III Maintenance Phase Withdrawal Phase Randomized, double-blind Open label

Investigational Drug

Placebo Placebo

• Withdrawal phase is open label – potential bias? • Fewer subjects exposed to investigational drug Maintenance Phase Withdrawal Phase Open label Randomized, Double-Blind

Investigational Drug

Placebo

• Subjects randomized to either placebo or gradual taper (staggered ratio) • Withdrawal phase double-blind; minimize bias • Allows for exploratory examination of treatment tapering – informative for phase III studies • Challenges and Limitations: • Treatment compliance • Sample size • Lack of rebound eﬀect

• Advantages • Conﬁned/intense monitoring • Healthy population –fewer confounders • Diverse measures

• In some cases, withdrawal/dependency is evaluated following drug discontinuation in phase III patient trials • Phase III studies in patients are limited in terms of available tools (e.g. pupilometers), trained staﬀ, and frequency of patient visits • Measures need to eﬃciently evaluate dependency and withdrawal

• More practical to administer: • Patient reported withdrawal scales • Adverse events • Clinician reported withdrawal scales (at scheduled visits)

• Less practical to administer: • Pupilometry • Cognitive / Psychomotor testing (e.g. Hopkins Verbal Learning Test) • Frequent clinician reported outcomes • Must have adequate exposure time (minimum 4 weeks) and follow up period of discontinuation (e.g. 5 x half life + 1-2 weeks) • Patient retention at end of study may be challenging • May incorporate into eﬃcacy studies where an active treatment vs placebo randomization phase follows an open label phase

Titration Open-label Double-Blind Tapering/End Phase Maintenance Phase Randomized Phase of Study Phase

Investigational Drug

Placebo Scale Clinician Rated Subject Rated Clinical Opiate Withdrawal Scale (COWS) Subjective Opiate Withdrawal Scale (SOWS) Physicians Withdrawal Checklist (PWC-20 and PWC-34) Benzodiazepine Withdrawal Symptom Questionnaire Clinical Institute Assessment of Withdrawal Benzodiazepines (CIAW-B) Ashton Rating Scale Amphetamine Withdrawal Scale (AWQ) Cocaine Selectivity Severity Assessment (CSSA) Cannabis Withdrawal Scale1 Discontinuation Emergent Signs and Symptoms Checklist (DESS)

1. Can be administered by either clinician or self report Scale Clinician Rated Subject Rated Hamilton Depression Rating Scale (HDRS) Montgomery-Asberg Depression Rating Scale (MADRS)1 Beck Depression Inventory Hospital Anxiety and Depression Scale (HADS) Hamilton Anxiety Rating Scale (HAM-A) Spielberger State Anxiety Inventory (SSAI) Short-form Pittsburgh Sleep Quality Index (PSQI) Leeds Sleep Evaluation Questionnaire (LSEQ) Epworth Sleepiness Questionnaire (LSEQ)

1. Self rated version of the scale (MADRS-S) available Scale Clinician Rated Subject Rated Uniﬁed Parkinson’s Disease Rating Scale (UPDRS) Uniﬁed Huntington Disease Rating Scale (UHDRS) Yale Global Tic Severity Scale (YGTSS) Berg Balance Test Score (BBT) Barnes Akathisia Rating Scale (BARS) Columbia-Suicide Severity Rating Scale (C-SSRS) • Standardized MedDRA* Query (SMQ) built from DSM-IV diagnostic criteria • “Drug withdrawal” SMQ (broad and narrow) captures only overt or diagnosed withdrawal syndrome • Too blunt for clinical trials

SMQ Term Drug withdrawal convulsions Drug rehabilitation Drug withdrawal headache Rebound eﬀect Drug withdrawal maintenance therapy Steroid withdrawal syndrome Drug withdrawal syndrome Withdrawal arrhythmia Drug withdrawal syndrome neonatal Withdrawal syndrome

*Medical Dictionary for Regulatory Activities Ubiquitous Withdrawal Symptoms Selective Withdrawal Symptoms Tremor Seizures Inﬂuenza-like symptoms Fatigue Hallucinations Myalgias Confused state Palpitations Sweating Hypertension Anorexia Flushing Fever Sleep Disturbance Poor Concentration Hypothermia Ataxia Agitation Abnormal movements Dizziness Abdominal cramps Restlessness Paresthesia Nausea Dilated pupils Depressed mood Vomiting Athralgias Headaches Anxiety Cold/Allergy URI symptoms Vertigo Irritability Diarrhea Parkinsonism

Agitation *Medical Dictionary for Regulatory Activities Yawning Confusion Myoclonus Piloerection • Withdrawal events are important safety assessments for drugs in development • Careful consideration needs to be given to select appropriate subject population • Pragmatic considerations need to be explored, particularly when withdrawal events are examined in Phase III studies ! Questions?

! Please contact me at: Beatrice Setnik, PhD INC Research Inc [email protected]

Evaluating drug dependence: regulatory, methodological and clinical challenges

Regulatory Considerations

Alicja Lerner, MD, PHD FDA, CDER, Controlled Substance Staﬀ White Oak, Maryland

The opinions and information in this presentation are those of the author and do not necessarily reﬂect the views and policies of the FDA

39 ! Below are deﬁnitions of dependence and addiction which were developed by American Society of Addiction Medicine (ASAM) and approved by the American Academy of Pain Medicine, the American Pain Society in 2001

! Physical dependence is a state of adaptation that is manifested by a drug class speciﬁc withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

! Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors inﬂuencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

1. Concern relates to 21 USC 812 (b):

For scheduling, the CSA requires a ﬁnding on relative abuse potential and relative dependence liability.

If the drug is a controlled substance or will be scheduled, we monitor abuse of the controlled substances and assess new data that relates to abuse and dependence liability from abuse.

41 2. Physical dependence is addressed in the label Section 9.3:

! To inform physicians about consequences of abrupt withdrawal at the end of treatment and about potential need for tapering to avoid potentially dangerous symptoms after abrupt withdrawal of the DRUG ! To inform physicians about potential consequences of abrupt withdrawal which might be necessary due to occurrence of serious adverse events caused by the DRUG, unexpected drug-drug interactions or due to lack of eﬃcacy; and to consider introduction of the drug with the similar action ! To inform physicians and institutions providing treatment to subjects abusing the DRUG about speciﬁc adverse events which can occur and might be expected as a consequence of abrupt DRUG withdrawal ! To inform drug abusers about health consequences of potential development of physical dependence and symptoms of DRUG withdrawal

1. Drug dependence related to substance use disorder includes known and well-deﬁned withdrawal syndromes such as opiate, benzodiazepine and stimulant withdrawal syndromes which are further described in DSM-5.

2. Broader spectrum of drug dependence that encompasses both:

! Drug dependence and withdrawal syndromes related to drugs of abuse ! Drug dependence and withdrawal syndromes related to unscheduled drugs, which include well-known withdrawal syndromes such as SSRIs, beta-blockers and corticosteroids.

43 44 Abrupt drug discontinuation may lead to various clinical manifestations:

1. Acute withdrawal syndrome - includes new signs and symptoms, which typically do not represent a relapse of the underlying condition, and are related to the disruption of neuro-regulatory changes (neuroadaptation) established during drug administration

2. Rebound - recurrence of symptoms of the treated disorder in patients, usually more severe than before the treatment

3. Post-acute withdrawal disorders - appearance of symptoms related to emerging new disorders

4. Relapse– return of a sign, symptom, or disease after a remission, occurring as a phenomenon in the natural history of the disease

5. Symptoms of drug toxicity - especially common with drugs with long half-lives; this fact emphasizes the need for drug plasma levels to diﬀerentiate from withdrawal symptoms

45 Chouinard G, Chouinard VA. New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal. Psychother Psychosom. 2015 Feb 21;84(2):63-71 46

1. New withdrawal symptoms include the symptoms that ﬁrst appeared during the drug discontinuation or dose decrease and are not part of the patient’s original illness

2. Diﬀerent classes of CNS drugs have some common withdrawal symptoms, but also have some speciﬁc to the drug class withdrawal symptoms

3. New withdrawal symptoms which are common to many CNS drug include nausea, anxiety, headaches, decreased concentration, irritability, agitation, tremor, sleep disturbances, dysphoria, depression

4. Some new withdrawal symptoms may be speciﬁc to a certain CNS drugs class: ! lacrimation, rhinorrhea, and sneezing for opiates ! electric shock sensations, confusion, myoclonus for SSRIs

5. The new withdrawal symptoms are usually transient and reversible

6. Major complications of abrupt withdrawal may occur such as seizures, suicide and psychoses

7. The onset of withdrawal symptoms depends on the drug’s duration of action; usually, short-acting drugs have an early peak of onset.

8. Drugs with higher potency and short/intermediate half-life have greater risks for withdrawal symptoms, and formation of drug dependence .

Chouinard G, Chouinard VA. New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal. Psychother Psychosom. 2015 Feb 21;84(2):63-71 47

Known withdrawal syndromes in diﬀerent drug classes of scheduled and unscheduled drugs Scheduled Drugs ! Opiates ! Benzodiazepines ! Stimulants (amphetamine, cocaine, methamphetamine,) ! Testosterone and androgenic anabolic steroids (AAS) ! Ketamine Unscheduled Drugs ! Antidepressants (“Prozac withdrawal syndrome”) ! Anti-parkinsonian drugs ! Anti-psychotics (Quetiapine, Clozapine) ! Beta-blockers ! Corticosteroids

48 ! Yawning, rhinorrhea, lacrimation, mydriasis, piloerection, vomiting, tremors, weight loss

! Increases in pulse, blood pressure, temperature, and respiratory rate, drug craving, anxiety, irritability, muscle and bone aches, hot and cold ﬂashes, nausea, and abdominal cramps

49 Drugs Half-lives: ! Heroin: 2-6 minutes ! Buprenorphine: 20–70 h, mean 37 hours ! Methadone: 7-65 hours

Peak severity of withdrawal ! Heroin - symptoms peak within 6 to 72 hours and last for 7 to 10 days ! Methadone - symptoms peak at 72 to 96 hours but last for 14 days or more ! Buprenorphine - symptoms are less severe and of shorter duration

Kosten TR, O‘Connor PG. Management of drug and alcohol withdrawal.. N Engl J Med. 2003 May 1;348(18): 50 1786-95 Withdrawal syndromes –Scheduled drugs Benzodiazepine withdrawal syndrome (in red are serious adverse events) Insomnia, hyperosmia, dizziness, headache, anorexia, muscular pain and stiﬀness, tremor, sweating, nausea and vomiting, tachycardia and palpitations, postural hypotension

Panic attacks, irritability, anxiety, confusion and cognitive diﬃculty, memory problems, hallucinations

Seizures, psychosis with hallucinations and delusions, suicide, homicidal ideation

Drug and Alcohol Withdrawal Clinical Practice Guidelines - New South Wales Health 2008 51

Withdrawal syndromes –Scheduled drugs Stimulants withdrawal syndrome

Phasal Model of Cocaine Withdrawal (T1/2 ~1 h) 'Crash' -onset within hours to a few days exhaustion hypersomnia no cravings to use dysthymia increased appetite restlessness irritability Withdrawal - 1-10 weeks lethargy anxiety Amphetamine, (T1/2 ~11 h) erratic sleep Crash strong craving typically commences 12–24 hours after last emotional liability amphetamine use, and subsides by days 2–4. irritability Withdrawal depression typically commences 2–4 days after last use, peaks in severity over 7–10 poor concentration days, and then subsides over 2–4 weeks. Extinction- up to 28 weeks Extinction episodic cravings weeks to months some dysphoria Australian Government Dept of Health. Models of intervention and care for psychostimulant users, April 2004 Gawin FH, Kleber HD: Abstinence symptomatology and psychiatric diagnosis in chronic cocaine abusers. Arch Gen Psychiat 43:107-113, 1986 52

! Rebound is a worsening of the symptoms of the treated disease after abrupt drug discontinuation, in comparison with the baseline pretreatment condition or ! Rebound is a rapid return of the patient’s original symptoms at a greater intensity than before treatment

Rebound can appear after discontinuation of any class of drugs regardless of the chemical structure or pharmacological action

Some well-known examples of rebound:

CNS-active drugs ! Benzodiazepines o rebound anxiety in patients treated for anxiety o rebound insomnia in patients treated for insomnia

! Stimulants (methylphenidate, dextroamphetamine) o rebound: deterioration of ADHD behaviors, irritability, deﬁance

53 ! Antipsychotics (clozapine, quetiapine) o rebound psychosis

! SSRIs (paroxetine, sertraline, ﬂuoxetine) o rebound: appearance of greater intensity of original symptoms: anxiety, panic, agitation, insomnia, depression, dysphoria, obsessions, compulsions

Cardiovascular drugs ! β-blockers (propranolol) o rebound: hypertension, severe tachycardia, angina, heart attack or even death due to myocardial infarction

New Rebound syndrome identiﬁed ! Immunomodulatory drugs for multiple sclerosis (ﬁngolimod, natalizumab) o rebound: may include severe reactivation of relapsing-remitting multiple sclerosis with unexpectedly severe clinical relapses accompanied by drastic increases in new or enhancing lesions seen on magnetic resonance imaging or increase in the development of new and enlarging T2 lesions in patients with MS enlarging T2

lesions in patients with MS Hatcher SE, Waubant E, Nourbakhsh B, Crabtree-Hartman E1, Graves JS. Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment. JAMA Neurol. 2016 May 2. Vellinga MM1, Castelijns JA, Barkhof F, Uitdehaag BM, Polman CH.Postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated 54 MS patients. Neurology. 2008 Mar 25;70(13 Pt 2):1150-1.

Rebound Phenomena - Examples Benzodiazepine: Rebound Anxiety in Patients Design: Double-blind, placebo-controlled study in 48 patients with anxiety . 4 weeks of BZ treatment followed by 3 weeks of abrupt withdrawal (16 patients ) or gradual drug withdrawal (14 patients), placebo group included 13 patients. BZ: diazepam 15 mg qd or bromazepam 18 mg qd Rebound anxiety was deﬁned as an increase of 10% or more above baseline total scores on both the Hamilton Rating Scale for Anxiety and the Self Rating Symptom Scale.

Results: The scores of patients withdrawn abruptly increased 10% or more on both the Hamilton Rating Scale for Anxiety and the Self Rating Symptom Scale. In patients with rebound anxiety previous anxiety symptoms returned and were more severe than before treatment, beginning in some cases within 24 hours of drug withdrawal; patients who dropped out of the study with rebound anxiety reported that they were incapacitated by the severity of their symptoms and unable to continue their regular work. There were no cases of rebound anxiety in 14 patients whose benzodiazepine was withdrawn gradually.

Fontaine R, Chouinard G, Annable L. Rebound anxiety in anxious patients after abrupt withdrawal of benzodiazepine treatment. Am J Psychiatry. 1984 Jul;141(7):848-52. 55 Post-acute-withdrawal syndrome (PAWS) also called persistent post-withdrawal syndrome or prolonged withdrawal syndrome describes a set of persistent impairments that occur after withdrawal from some drug classes such as benzodiazepines, antipsychotics, antidepressants, opiates. The characteristic feature of these disorders is length of duration sometimes persisting for months and years after cessation of the drug; also, these are frequently new disorders.

Examples of post-acute withdrawal syndromes include:

! Antipsychotics: tardive dyskinesia and supersensitivity psychosis

! Benzodiazepines: protracted insomnia, anxiety, tinnitus. depression, paresthesia, memory impairment, formication, muscle spasms, tremor, blepharospasm, and psychosis

! SSRIs: major depression, bipolar disorders, anxiety disorders, panic attacks, tardive insomnia, bulimia

! Opiates: memory problems, inability to think clearly, fatigue, anxiety, depression, insomnia, intense cravings to use opiates, drug dreams, hostility, anhedonia

56 Population ! Patients for whom the drug will be prescribed (preferred) ! If not possible to perform the study in patients population due to safety concerns (rebound psychosis or withdrawal seizures in epilepsy patients ), then healthy volunteers can be used ! Healthy Volunteers, age 18-55 y.o. usually, however in some cases elderly > 55 y.o. if the drug will be prescribed for this age group ! Number of subjects who completed the study should be adequate to show statistical signiﬁcance…

Design " Placebo arm should be included " Maintenance phase – 2 arms: drug and placebo, double blind " During the withdrawal period placebo should be used for both arms drug to blind for potential eﬀect of withdrawal

Dose " Highest tolerated therapeutic dose

! Treatment time: ~ 4 weeks, depends on T1/2 and time to steady state (~3weeks) ! Time of withdrawal: usually total up to 3-4 weeks, but depends on T1/2, and up to 6 weeks follow-up weekly phone calls, to check for rebound and PAWS ! Pharmaco-Dynamic Scales - administration time points ! Baseline, last day ON-drug, 1st day OFF-drug, then varies with T1/2 but usually more frequent during the ﬁrst week of discontinuation (3-4 times), then 2-3 times a week ! AEs collection ! During the treatment phase and the withdrawal phase, reported separately ! Blood sampling: for PD-PK correlation

! Time points: to follow the PD time-points ! Rationale for PK evaluation: o Distinguish between AEs due to drug toxicity vs withdrawal symptoms o Symptoms are sometimes identical, so PK is critical to provide clariﬁcation • Example 1: nausea/vomiting - common AE in drug toxicity but also during withdrawal • Example 2: in epilepsy population seizure after drug withdrawal could be due to the disorder or a withdrawal symptom (withdrawal seizures)

58 ! Opiates withdrawal scales o Clinical Opiate Withdrawal Scale (COWS) o Subjective Opiate Withdrawal Scale (SOWS) ! Benzodiazepines withdrawal scales: o Physicians Withdrawal Checklist PWC-20 and PWC-34 o Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) o Clinical Institute Assessment of Withdrawal Benzodiazepines (CIAW-B) o Ashton Rating Scale ! Stimulants withdrawal scales: o Amphetamine Withdrawal Questionnaire (AWQ) o Cocaine Selective Severity Assessment (CSSA) ! Cannabinoids withdrawal scale: o Cannabis Withdrawal Scale ! SSRI withdrawal scale o Discontinuation Emergent Signs and Symptoms Checklist (DESS)

It is recommended that already validated scales are used

! Columbia-Suicide Severity Rating Scale (C-SSRS) ! Depression Scales o Hamilton Depression Rating Scale (HDRS) o Montgomery-Asberg Depression Rating Scale (MADRS) o Beck Depression Inventory o Hospital Anxiety and Depression Scale (HADS)

! Anxiety Scales o Hamilton Anxiety Rating Scale (HAM-A) o Spielberger State Anxiety Inventory (SSAI) Short-form

" Sleep scales o Pittsburgh Sleep Quality Index (PSQI) o Leeds Sleep Evaluation Questionnaire (LSEQ) o Epworth Sleepiness Scale (ESS)

60 These scales are particularly helpful in assessment of rebound phenomena but also withdrawal Neurological disorders scales ! Unified Parkinson’s Disease Rating Scale (UPDRS) ! Unified Huntington’s Disease Rating Scale (UHDRS) ! Unified Dystonia Rating Scale (UDRS) ! Yale Global Tic Severity Scale (YGTSS) ! Barnes Akathisia Rating Scale (BARS)

Psychiatric disorders scales ! Depression scales ! Anxiety Scales ! ADHD scales ! Schizophrenia Scales

61 ! Safety considerations o This is a Phase I study and all precautions and safeguards should be in place o Either the whole study or at least the critical parts of the study should be performed in inpatient setting, which includes initial dose escalation and then abrupt withdrawal o During the outpatient phase the subjects should be informed how to contact the site in case of AEs o Subjects discontinuation criteria should be based on the previous safety data from Phase 1, 2 and 3 studies.

! Ethical dilemmas o In relation to the development of dependence it has to be emphasized that dependence does not equal addiction, and the withdrawal AEs have only limited duration o Some drugs should be excluded from dependence studies in healthy subjects such as mu-opioid receptor agonists or BZ-like drugs

62 1. It is preferable that dependence and withdrawal are evaluated after chronic drug exposure in Phase 2 or 3 in patients at conclusion of the clinical study , if possible.

2. A separate clinical dependence study is to be conducted only in absence of data from Phase 2 or 3 study, e.g., if it is too late in the drug development program to perform evaluation of dependence at the conclusion of the Phase 2 or 3 study

3. The sponsor should plan these studies in advance, even in pre-IND stage and contact the Agency on how to implement evaluation of dependence and withdrawal during Phase 2 and Phase 3 clinical studies

4. Additionally, it is noted that in some clinical programs during the drug development it is not acknowledged that the drug causes dependence and a withdrawal syndrome. The withdrawal syndrome may be incorrectly referred to as a “discontinuation syndrome.” However, physical dependence and withdrawal are important safety and abuse-related issue and should not be dismissed easily.

63 64

! Ashton H. Protracted withdrawal syndromes from benzodiazepines. J Subst Abuse Treat. 1991;8(1-2):19-28. Review. ! Australian Government Dept of Health. Models of intervention and care for psychostimulant users, 2nd edition - monograph series no. 51, April 2004 ! Bhanji NH1, Chouinard G, Kolivakis T, Margolese HC. Persistent tardive rebound panic disorder, rebound anxiety and insomnia following paroxetine withdrawal: a review of rebound-withdrawal phenomena. Can J Clin Pharmacol. 2006 Winter; 13(1):e69-74. Epub 2006 Jan 23. ! Chouinard G, Chouinard VA. New Classiﬁcation of Selective Serotonin Reuptake Inhibitor Withdrawal. Psychother Psychosom. 2015 Feb 21;84(2):63-71. ! Chouinard G. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry. 2004;65 Suppl 5:7-12. Review. ! Curran HV, Bond A, O'Sullivan G, Bruce M, Marks I, Lelliot P, Shine P, Lader M. Memory functions, alprazolam and exposure therapy: a controlled longitudinal study of agoraphobia with panic disorder. Psychol Med. 1994 Nov;24(4):969-76. ! Drug and Alcohol Withdrawal Clinical Practice Guidelines - New South Wales Health 2008 ! DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) American Psychiatric Association. Arlington, VA: American Psychiatric Publishing ! Fava GA, Gatti A, Belaise C, Guidi J, Oﬃdani E. Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review. Psychother Psychosom. 2015 Feb 21;84(2):72-81

65 ! Gawin FH, Kleber HD: Abstinence symptomatology and psychiatric diagnosis in chronic cocaine abusers. Arch Gen Psychiat 43:107-113, 1986 ! Fontaine R, Chouinard G, Annable L. Rebound anxiety in anxious patients after abrupt withdrawal of benzodiazepine treatment. Am J Psychiatry. 1984 Jul;141(7):848-52. ! Hatcher SE, Waubant E, Nourbakhsh B, Crabtree-Hartman E1, Graves JS. Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment. JAMA Neurol. 2016 May 2. ! Kales A, Soldatos CR, Bixler EO, Kales JD. Rebound insomnia and rebound anxiety: a review. Pharmacology. 1983;26(3): 121-37. Review. ! Lupolover R, Dazzi H, Ward J. Rebound phenomena: results of a 10 years' (1970--1980) literature review. Int Pharmacopsychiatry. 1982;17(4):194-237. ! Margolese HC, Chouinard G, Beauclair L, Bélanger MC.Therapeutic tolerance and rebound psychosis during quetiapine maintenance monotherapy in patients with schizophrenia and schizoaﬀective disorder. J Clin Psychopharmacol. 2002 Aug; 22(4):347-52. ! Riccio CA, Waldrop JJ, Reynolds CR, Lowe P.Eﬀects of stimulants on the continuous performance test (CPT): implications for CPT use and interpretation. J Neuropsychiatry Clin Neurosci. 2001 Summer;13(3):326-35. Review. ! Smith DE, Wesson DR. Benzodiazepine dependency syndromes. J Psychoactive Drugs. 1983 Jan-Jun;15(1-2):85-95. ! Smucker WD, Hedayat M (September 2001). "Evaluation and treatment of ADHD ! Vellinga MM1, Castelijns JA, Barkhof F, Uitdehaag BM, Polman CH.Postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated MS patients. Neurology. 2008 Mar 25;70(13 Pt 2):1150-1.

I am an employee of INC Research and oversee the conduct of clinical trials in our Phase I unit in Toronto, Ontario.

3400 BC - Opium poppies cultivated in Mesopotamia 1000 BC - Opium present in EU and Northern Africa 400 BC - Hippocrates – medicinal use of poppy juice 970 - Chinese use opium for dysentery 1806 - Morphine isolated 1827 - Merck , begins commercial manufacturing of morphine 1844 - Heroin synthesized Early 1900s - Campaign to supply free samples of heroin through the mail to morphine addicts trying give up their habits 1903 - Heroin addiction rises to alarming rates. 1914 - Harrison Narcotics Act 1952 & 68 - Addiction Classiﬁed as a personality disorder in DSM-I and II 1980 - DSM-III Substance use disorders listed as substance abuse & substance dependence 1994 - DSM-IV one can only be diagnosed with substance abuse in the absence of substance dependence. 2013 - DSM-V Substance Use Disorder

Time for a uniﬁed approach:

- Prescribers need to know about dependency potential and withdrawal eﬀects

- Where available information is inconsistent

- Increasing number of internet tools and apps may lead to mis- information

80 y.o. Female Admitted to Nursing Home

Alzheimer’s dementia x 3 years with BPSD and increasing confusion Depression Chronic back pain due to OA CAD, HPTN Osteoporosis Insomnia

Ativan 1 mg qHS Escitalopram 10 mg qd Codeine 30 mg + acetaminophen TID Aricept 10 mg qd Metoprolol 12.5 mg BID Seroquel 12.5 mg TID prn Alendronate ASA EC Ramipril Vitamin D Ativan 1 mg qHS Escitalopram 10 mg qd Codeine 30 mg + acetaminophen TID Aricept 10 mg qd Metoprolol 12.5 mg BID Seroquel 12.5 mg TID prn Alendronate ASA EC Ramipril Vitamin D In the context of increased confusion, several should be stopped. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Lexapro® safely and eﬀectively ------WARNINGS AND PRECAUTIONS------Clinical Worsening/Suicide Risk: Monitor for clinical worsening, suicidality and unusual change in behavior, especially, during the initial few months of therapy or at times of dose changes (5.1). -Serotonin Syndrome: -Discontinuation of Treatment with Lexapro: A gradual reduction in dose rather than abrupt cessation is recommended whenever possible (5.3).

5.3 Discontinuation of Treatment with Lexapro During marketing of Lexapro and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Lexapro. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.4)].

9.2 Abuse and Dependence Physical and Psychological Dependence Animal studies suggest that the abuse liability of racemic citalopram is low. Lexapro has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. The premarketing clinical experience with Lexapro did not reveal any drug-seeking behavior. However, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate Lexapro patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

Physical and Psychological Dependence The use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence. The risk of dependence increases with higher doses and longer term use and is further increased in patients with a history of alcoholism or drug abuse or in patients with significant personality disorders. The dependence potential is reduced when lorazepam is used at the appropriate dose for short-term treatment. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving lorazepam or other psychotropic agents. In general, benzodiazepines should be prescribed for short periods only (e.g., 2 to 4 weeks). Extension of the treatment period should not take place without reevaluation of the need for continued therapy. Continuous long-term use of product is not recommended. Withdrawal symptoms (e.g., rebound insomnia) can appear following cessation of recommended doses after as little as one week of therapy. Abrupt discontinuation of product should be avoided and a gradual dosage-tapering schedule followed after extended therapy. Abrupt termination of treatment may be accompanied by withdrawal symptoms. Symptoms reported following discontinuation of benzodiazepines include headache, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, rebound phenomena, dysphoria, dizziness, derealization, depersonalization, hyperacusis, numbness/tingling of extremities, hypersensitivity to light, noise, and physical contact/ perceptual changes, involuntary movements, nausea, vomiting, diarrhea, loss of appetite, hallucinations/delirium, convulsions/seizures, tremor, abdominal cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, vertigo, hyperreflexia, short-term memory loss, and hyperthermia. Convulsions/seizures may be more common in patients with pre-existing seizure disorders or who are taking other drugs that lower the convulsive threshold such as antidepressants. There is evidence that tolerance develops to the sedative effects of benzodiazepines. Lorazepam may have abuse potential, especially in patients with a history of drug and/or alcohol abuse.

Substance abuse Because codeine is an opiate agonist, acetaminophen + codeine is subject to substance abuse and psychologic dependence (i.e., drug addiction) or criminal diversion. Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk for harm. Patients with a previous history of substance abuse may be at increased risk of relapse if treated with acetaminophen + codeine. Abuse and addiction are separate and distinct from physiologic dependence and tolerance. Physicians should be aware that psychologic dependence may not be accompanied by concurrent tolerance and symptoms of physiologic dependence. In addition, abuse of opiate agonists can occur in the absence of true psychologic dependence and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Health care professionals should not let concerns over psychologic dependence deter them from using adequate amounts of opiate agonists in the management of severe pain. Patients should also be counseled regarding misconceptions regarding the use of opiate agonists for pain management. Acetaminophen; codeine is not approved for the management of substance abuse (alcohol or drug dependence). Abrupt discontinuation Abrupt discontinuation of prolonged acetaminophen +codeine therapy can result in withdrawal symptoms (see Adverse Reactions). Patients should be gradually tapered oﬀ acetaminophen+ codeine to avoid a withdrawal reaction. Generally, a 50% decrease every 1—2 days of the daily acetaminophen+ codeine dose will prevent withdrawal symptoms in patients who have been receiving large daily doses of codeine.

Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. TYLENOL® with Codeine should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If TYLENOL® with Codeine is abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Acute Withdrawal (discontinuation) Symptoms: Acute discontinuation symptoms such as insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability, have been described after abrupt cessation of antipsychotic drugs including quetiapine. Gradual withdrawal over a period of at least one to two weeks is advisable. Symptoms usually resolved after 1 week postdiscontinuation.

Abrupt discontinuation Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's disease and the elderly. Diagnosis should be made according to current guidelines. Therapy with donepezil should only be started if a caregiver is available who will regularly monitor drug intake by the patient. The use of donepezil has not been investigated in patients with other types of dementia, or in patients with other types of memory impairment (e.g., age-related cognitive decline). Avoid abrupt discontinuation of therapy where possible to limit sudden decline in cognitive function or increase in behavioral disturbances. Although patients with Alzheimer's disease and other dementias commonly lose weight, cholinesterase inhibitors, including donepezil, have been associated with weight loss in these patients. During therapy, weight must be monitored.

- Substance Use Disorder is ravaging our communities

- The drug dependency proﬁle of prescribed medications is largely ill- described

- Prescribers and their patients will be well served by further studies designed to evaluate the potential for dependency and withdrawal eﬀects of medications.