November 12, 2012

Buprenorphine and Related Dynamics in a

Clinical Setting

Dean Babcock, MSW, LCSW, LCACAssociate Vice President

Midtown Community Mental Health Center

• High affinity partial mu opioid agonist and kappa-opioid antagonist prevents withdrawal, high, reduces craving; advantage: very low risk from overdose– Has effects of typical opioid agonists at lower doses – Produces a ceiling effect at higher doses– Binds to opioid receptors and is long-acting

• Dose: Typically 12-16 mg/day, initiated while patient is in mild to moderate withdrawal, prescribed by physicians who have completed a certification process– Slow to dissociate from receptors so effects last even if one daily dose is

missed.

Buprenorphine

• Formulations: Buprenorphine only (Subutex), combined with naloxone (4:1; Suboxone); film• Each 8 mg tablet contains 2 mg of naloxone• Each 2 mg tablet contains 0.5 mg of naloxone

• Sublingual tablet• Dissolvable film• Implantable

• Results: Very effective in reducing illicit opioid use• FDA approved for use with opioid dependent persons

aged 16 and older• Side effects: Constipation, drowsiness, headache

Buprenorphine

ProbuphineBuprenorphine Implants

Clinical trials have indicted that buprenorphine implantsare effective in the treatment of opioid dependence over a 24 week period following implementation.

JAMA, Oct 13, 2012

Titan Pharmaceuticals Inc. has submitted a New Drugapplication to the FDA . This is the first implantableFormation of Buprenorphine that can provide six Months of medication following a single treatment.

Suni Bhonole Titan Pharmaceuticals, Oct 2012

Potentially lethal dosePositive effect

=

addictive

potential

Full agonist -morphine/heroinhydromorphone

Antagonist - naltrexone

Agonist + partial agonistPartial agonist - buprenorphine

Mu efficacy and opiate addiction

fentanyl

Buprenorphine is EFFECTIVE

• Buprenorphine is as effective as moderate doses of methadone (Fischer et al., 1999; Johnson, Jaffee, &Fudula, 1992; Ling et al., 1996; Schottenfield et al., 1997; Strain et al., 1994)

• Buprenorphine's partial agonist effects make it mildly reinforcing, encouraging medication compliance (Ling et al., 1998)

• After a year of buprenorphine plus counseling, 75% of patients retained in treatment compared to 0% in a placebo-plus-counseling condition (Kakko et al., 2003)

LOW RISK PROFILE OF BUPRENORPHINE

• Less risk of respiratory depression• Lower level of physical dependence• Lower level of abuse• Discourages IV use• Diminished street value/diversion• Dosing flexibility 1-3 days

BARRIERS TO BUPRENORPHINE

• Just learning about it, training underway• STIGMA• Reluctance to use medications• Medication alone is just not enough• Cost ($8.00 a day)• Formulary• Reluctance of medical community• Misuse and diversion

Who can prescribe buprenorphine?

Physicians who have received buprenorphine training andobtained a federally approved waiver can prescribeSubutex and Suboxone or approved generic equivalent

What are the adverse effects of buprenorphine abuse?

According to the manufacturer’s safety information forSuboxone, buprenorphine “can cause serious life-threatening respiratory depression and death, particularlywhen taken by the intravenous (IV) route in combinationwith benzodiazepines or other central nervous system(CNS) depressants (i.e., sedatives, tranquilizers, oralcohol).” They also note that “intravenous misuse or

taking[Suboxone] . . . before the effects of full-agonist opioids(e.g., heroin, hydrocodone, methadone, morphine,oxycodone) have subsided is highly likely to cause opioidwithdrawal symptoms.” In addition, “chronic use ofbuprenorphine can cause physical dependence.”

Weiss, R.D., et. al., “Adjunctive Counseling During Brief and Extended Buprenorphine-Naloxone Treatment for Prescription Opioid Dependence,” Archives of General Psychiatry, Online First November 7, 2011

“Patients dependent on prescription opioids . . . are most likely to reduce their opioid use during the first several months of treatment while receiving buprenorphine-naloxone; if tapered off this medication, the likelihood of relapse to opioid use or dropout from treatment is overwhelmingly high” (p. E7).

The amount of buprenorphine legally available for distribution and sale has increasedDistribution of buprenorphine to retail and dispensinginstitutions (such as pharmacies, hospitals, practitioners,teaching institutions, researchers, analytical labs, andNarcotic treatment programs) has increased from 13,475 in2003 to 1,451,503 in 2010. The number of patientsreceiving a prescription for Subutex® or Suboxone® fromU.S. outpatient retail pharmacies increased from slightlyless than 20,000 in 2003 to more than 600,000 in 2009.

(Source: CESAR FAX,Vol. 20, Iss. 22 & 23)

The number of buprenorphine drug items secured in law enforcement operations and analyzed by state and local forensic laboratories has increased from 21 in 2003 to 8,172 in 2009

• Buprenorphine has been smuggled into state prisons, including those in Maine, Massachusetts, New Jersey, New Mexico, Pennsylvania, and Vermont

• More than one-half of buprenorphine-related emergency department (ED) visits are for the nonmedical use of the drug.

• The estimated number of ED visits related to the nonmedical use of buprenorphine has more than tripled, from 4,440 in 2006 to 14,266 in 2009.

U.S. Drug Enforcement Agency (DEA), Office of Diversion Control, Special Report: Methadone and Buprenorphine, 2003-2008, 2009

0

2000

4000

6000

8000

10000

12000

2003 2004 2005 2006 2007 2008 2009

6,397

7,303

9,822

10,77410,459

10,361

21

8,172

5,627

3,108

1,809

540262

Estimate Number of Total Methadone and Buprenorphine Drug Item Analyzed by State and Local Forensic Laboratories

in the U.S., 2003-2009

4,967

Methadone

Buprenorphine

Nearly All Emergency Department Visits for the Accidental Ingestion of Buprenorphine Occur in

Children Under the Age of Six

Substance Abuse and Mental Health Services Administration (SAMHSA), Drug Abuse Warning Network (DAWN), National Estimates of Drug-Related Emergency Department Visits, 2004-2009

0

2000

4000

6000

8000

10000

12000

2003 2004 2005 2006 2007 2008 2009

Estimated Number of Total Methadone and Buprenorphine Drug Items Analyzed by State and Local Forensic Laboratories in the US, 2003-2009

Methadone

Buprenorphine

Estimated Number of Buprenorphine- and Hydromorphone-Related ED Visits More Than Doubles from 2006 to 2010

Buprenorphine 2006 2010(Suboxone, Subutex, Temgesic, Buprenex) 4,440 15,778 +255%

Adapted by CESAR from Substance Abuse and Mental Health Services Administration (SAMHSA), National Estimates of Drug-Related Emergency Department Visits, 2004-2010

Drug name # of ED Visits for % Change(Common Brand Name) Nonmedical Use 2006 to 2010

Adapted by CESAR from Johanson, C-E; Arfken, C. L.; di Menza, S.; and Schuster, C. R., “Diversion and Abuse of Buprenorphine: Findings from National Surveys of Treatment Patients and Physicians,” Journal of Drug and Alcohol Dependence 120:190-195, 2012.

Perceptions of Buprenorphine Diversion/Misuse, Physicians Federally Certified to Prescribe Buprenorphine

(n=8,194 from 2005 to 2009)

Majority of Buprenorphine-Certified Physicians Think Buprenorphine Is Easier to Get Illegally Than Methadone

61% of Buprenorphine-Related Emergency Department Visits for Nonmedical use

Substance Abuse and Mental Health Services Administration (SAMHSA), Drug Abuse Warning Network, 2009: Selected Tables of National Estimates of Drug-related Emergency Department

• Taking more than the prescribed dose• Taking buprenorphine prescribed for another individual• Deliberate poisoning with buprenorphine by another person• Documented misuse or abuse of buprenorphine

• Childhood poisoning• Individuals who take a wrong medication by mistake• Caregiver administering the wrong medicine by mistake

• Adverse reactions• Drug-drug interactions• Drug-alcohol interactions resulting from using buprenorphine for therapeutic purposes

• Seeking substance abuse treatment• Drug rehabilitation• Medical clearance for admission to a drug treatment or detoxification unit

Reckitt Benckiser Pharmaceuticals Inc. to Voluntarily Discontinue the Supply of Suboxone Tablets (buprenorphine and naloxone sublingual tablets

The company received an analysis of data form U.S. PoisonControl Centers on September 15,2012 that foundconsistently and significantly higher rates of accidentalunsupervised pediatric exposure with Suboxone Tablets (buprenorphine and naloxone sublingual tablets [CIII] thanseen with Suboxone Film (buprenorphine and naloxonesublingual form [CIII]. The rates for Suboxone Tablets were7.8-8.5 times greater depending on the study period.

September 25, 2012

PATIENT PERCEPTIONS

1) Fight Withdrawal

• “[Some users] don’t want to get off [opioids] for good. They just want to not be sick, so they have Suboxone stashed away for when they feel sick”

(TP, p. 115).

• “They [opiate addicts] use it … like Tylenol 3®, to use till they can get a fix. [Suboxone is] a drug of convenience” (TP, p. 83).

• “Some start off using it …to assist with withdrawal, but find that they like how it feels and become addicted” (TP, p. 34).

• “I quartered them [Suboxone] …to take the bare minimum, so I wouldn’t be sick, but that way I could still use an opiate; I would buy them …to come off other stuff, but it never worked that way. ‘Cuz you could get high off

Suboxone if you hadn’t had any opiates in a couple of days .

• If you are addicted to opiates, you take the smallest piece of Suboxone—it makes you feel normal” (U, p. 133).

Department of Alcohol and Drug Addiction Services, Ohio Substance Abuse Monitoring Network: Surveillance of Dug Abuse Trends in the State of Ohio, January-June 2011

2) Get High

• “If you are clean [opioid free], you will get very high from Suboxone” (U, p. 17).

• “For a buzz … can snort Suboxone, as long as you don’t have other opiates in the system” (U, p. 50).

• “If you are not addicted to opiates and you take a Suboxone, it’s very, very strong. It can make you high for three days” (U, p. 133).

• “People … will use Xanax® a half-hour before Suboxone and will get high.

• Some clients say the effects are as good as, or better than, that of OxyContin®” (TP, p. 17).

• “[A] lot of people are being introduced to opioids through Suboxone now because, if they were not Suboxone users, the buprenorphine … the active agent in Suboxone is giving them the opiate effect, and now they’re looking

for stronger opioids.

PATIENT PERCEPTIONS

Department of Alcohol and Drug Addiction Services, Ohio Substance Abuse Monitoring Network: Surveillance of Dug Abuse Trends in the State of Ohio, January-June 2011

3) Avoid Detection

• “Participants also reported that individuals who need to avoid detection of drug use on urine drug screens (probationers) use Suboxone because it is often not screened” (Report, p. 4). “[Suboxone is] the institutional drug of choice” (U, p. 17).

PATIENT PERCEPTIONS

Department of Alcohol and Drug Addiction Services, Ohio Substance Abuse Monitoring Network: Surveillance of Dug Abuse Trends in the State of Ohio, January-June 2011

“People typically put them …under their tongue, or theychew them up. I’ve actually witnessed a couple peopleshoot [inject] them up; I would eat the full 8 mg Suboxone”(U, p. 132). “I snorted it … when I would take it. It made menot sick” (U, p. 132). “Well, I shoot [Suboxone] in my neck,so, um, it goes straight to you, you know” (U, p. 133). “I do know a few people that when switched to the films[Suboxone strips], they say that those are a lot easier toshoot up [inject]. Yeah, ‘cause they dissolve in water; theydissolve completely, and I’ve heard people say that thoseactually work really well” (U, p. 133).

How is Suboxone Being Used?

Department of Alcohol and Drug Addiction Services, Ohio Substance Abuse Monitoring Network: Surveillance of Drug Abuse Trends in the State of Ohio, January-June 2011, 2011

Practical Objectives from the field

• Need closer monitoring• Use of INSPECT REPORTS (pharmacy driven data on scheduled drug

prescriptions filled by pharmacies)

• High doses• Split doses• Securing of medications• Desire for drug – but not treatment• Interface with primary care medicine and large populations of

opiate prioritized patients, chronic pain, acute pain, addiction.

Policy changes that may decrease buprenorphine diversion and misuse

• The apparent increase in buprenorphine availability, diversion, and nonmedical use suggest the need for buprenorphine policy changes.

• Current testing protocols, including those of medical examiners and drug testing programs, should include routine testing for buprenorphine to estimate the full magnitude of and to monitor buprenorphine diversion and misuse.

• Physician education programs for prescribing buprenorphine, especially strategies to detect and deter diversion and misuse, need to be strengthened.