KAP Keys
For Physicians
Based on TIP 40
Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Substance Abuse and Mental Health Services Administration
Center for Substance Abuse Services
www.samhsa.gov

Introduction

KAP Keys were developed to accompany the Treatment Improvement Protocol (TIP) Series published by the Center for Substance Abuse Treatment (CSAT), Substance Abuse and Mental Health Services Administration. These KAP Keys are based entirely on TIP 40 and are designed to meet the needs of the busy physician for concise, easily accessed how-to information.

For more information on the topics in these KAP Keys, readers are referred to TIP 40.

Other Treatment Improvement Protocols (TIPs) that are relevant to these KAP Keys:

TIP 16: Alcohol and Other Drug Screening of Hospitalized Trauma Patients (1995) BKD164
TIP 24: A Guide to Substance Abuse Services for Primary Care Clinicians (1997) BKD234
TIP 28: Naltrexone and Alcoholism Treatment (1998) BKD268
TIP 43: Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Programs (2005) BKD524

Dosage Forms of Buprenorphine Available in the United States (as of July 2004)
KAP Keys Based on TIP 40

Medication
Trade Name
Dosage Form(s)
Indication
Company
FDA Approved for Opioid Addiction Treatment
Buprenorphine
Subutex
2- or 8-mg 
sublingual tablets
Opioid addiction
Reckitt Benckiser
Yes
Buprenorphine/
naloxone 
combination
Suboxone
2- or 8-mg 
sublingual tablets with buprenorphine/
naloxone in 4:1 ratio
Opioid addiction
Reckitt Benckiser
Yes
Buprenorphine
Buprenex
Injectable ampules
Moderate-to-severe pain
Reckitt Benckiser
No
Buprenorphine
Buprenorphine injectable
(generic)
Injectable ampules
Moderate-to-severe pain
Abbott Laboratories
No

Drug Interactions

Benzodiazepines and Other Sedative Drugs
	Buprenorphine plus sedative-hypnotics (including alcohol) may cause serious depression of the central nervous 
system. 
	If simultaneous treatment with buprenorphine and sedative-hypnotics is necessary, the doses of both medications may need to be lowered. 
Medications Metabolized by Cytochrome P450 3A4
	Buprenorphine is metabolized by the cytochrome 
P450 3A4 enzyme system. 
	Other medications that interact with this enzyme 
system should be used with caution in patients taking buprenorphine. 
	A continuously updated list of cytochrome P450 3A4 
drug interactions is available at 
medicine.iupui.edu/flockhart/table.htm.
Opioid Antagonists
	Buprenorphine treatment should not be combined with 
opioid antagonists (e.g., naltrexone). 
	Naltrexone can precipitate an opioid withdrawal syndrome 
in patients maintained on buprenorphine.
Opioid Agonists
	Full agonists may not provide adequate analgesia in patients stabilized on maintenance buprenorphine. 
	If use of a full mu agonist is needed for pain relief in a patient maintained on buprenorphine, the buprenorphine should be discontinued until the pain can be controlled without the use of opioid pain medications. 

Components of a Complete Substance Abuse Assessment

	Substance use history (e.g., age of first use; substances used; change in effects over time; history of tolerance, overdose, withdrawal; attempts to quit; current problems with compulsivity or cravings) 
	Addiction treatment history (e.g., previous treatments for addiction, types of treatments tried, outcomes of treatment attempts) 
	Psychiatric history (e.g., patients diagnoses, psychiatric treatments recommended/attempted, outcomes of treatments) 
	Family history (e.g., substance use disorders in family, family medical and psychiatric histories) 
	Medical history (e.g., detailed review of systems, past medical/surgical history, sexual history [for women, likelihood of pregnancy], current and past medications, pain history) 
	Social history (e.g., quality of recovery environment, family/living environment, substance use by members of support network) 
	Readiness to change (e.g., patients understanding of his or her substance use problem, patients interest in treatment now, whether treatment is coerced or voluntary)

Recommended Baseline Laboratory Evaluation of Patients Who Are Addicted to Opioids

	Serum electrolytes 
	BUN and creatinine 
	CBC with differential and platelet count 
	Liver function tests (GGT, AST, ALT, PT or INR, albumin) 
	Lipid profile 
	Urinalysis 
	Pregnancy test (for women of childbearing age) 
	Toxicology tests for drugs of abuse 
	Blood alcohol level (using a breath-testing instrument or a blood sample) 
	HIV antibody testing
	Hepatitis B virus (HBV) and hepatitis C virus (HCV) screens
	Serology test for syphilisVenereal Disease Research Laboratories (VDRL)
	Purified protein derivative (PPD) test for tuberculosis, preferably with control skin tests

Signs of Opioid Intoxication and Withdrawal

Syndrome
Physical Findings
Opioid intoxication
Conscious
Sedated, Drowsy
Slurred Speech
Nodding or intermittently dozing
Memory Impairment
Mood Normal to euphoric
Pupillary constriction
Opioid overdose
Unconscious 
Pinpoint pupils
Slow, shallow respirations
   (respirations below 10 per minutes)
Pulse rate below 40 per minut
Overdose triad: apnea, coma,
   pinpoint pupils (with terminal anoxia: 
    fixed and dilated pupils)

Staging and Grading Opioid  Withdrawal

Stage of Withdrawal
Grade
Physical Signs/Symptoms
Early withdrawal
(824 hours after last use)

1
Lacrimation and/or rhinorrhea 
Diaphoresis 
Yawning 
Restlessness
Insomnia

2
Dilated pupils 
Piloerection 
Muscle twitching 
Myalgia 
Arthralgia 
Abdominal pain
Fully developed 
withdrawal
(13 days 
after last use)

3
Tachycardia 
Hypertension 
Tachypnea 
Fever 
Anorexia or nausea
Extreme restlessness

4
Diarrhea and/or vomiting
Dehydration 
Hyperglycemia 
Hypotension
Curled-up position

Assessing Appropriateness for Buprenorphine Treatment

Before a candidate is approved for buprenorphine treatment for opioid addiction, he or she should, at a minimum,

	Have an objectively ascertained diagnosis of opioid addiction (compulsive use of opioids despite harm), otherwise known as opioid dependence as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
	Be interested in treatment for opioid addiction 
	Have no absolute contraindication (i.e., known hypersensitivity) to buprenorphine (or to naloxone if treating with the buprenorphine/naloxone combination) 
	Be expected to be reasonably compliant with buprenorphine treatment 
	Understand the risks and benefits of buprenorphine treatment 
	Be willing to follow safety precautions for buprenorphine treatment 
	Agree to buprenorphine treatment after a review of treatment options

A candidate for buprenorphine treatment for opioid 
addiction should not have 

	Comorbid dependence on high doses of benzodiazepines or other central nervous system depressants (including alcohol) 
	Significant untreated psychiatric comorbidity 
	Active or chronic suicidal or homicidal ideation or attempts 
	Multiple previous treatments for drug abuse with frequent relapses (except that multiple previous attempts at detoxification with subsequent relapse may be a strong indication for long-term maintenance treatment) 
	Poor response to previous well-conducted attempts at buprenorphine treatment 
	Significant medical complications 
	Conditions that are outside the treating physicians expertise 

Buprenorphine should be used with caution with patients who

	Are being treated for seizure disorders
	Are taking HIV antiretroviral medications
	Have hepatitis or otherwise impaired hepatic function
	Are pregnant
	Are dependent on or abusing alcohol or drugs other than opioids

Treatment Protocols
Induction Days 12: Short-Acting Opioids
Treatment Protocols
Induction Days 12: Long-Acting Opioids
Treatment Protocols
Induction Day 2 Forward

*If buprenorphine monotherapy was administered on day 1, switch to buprenorphine/naloxone on day 2 (for a patient who is not pregnant).
Dose may be increased by 2/0.54/1 mg increments on subsequent days as needed for symptom relief. Target dose is 12/316/4 mg buprenorphine/naloxone per day by the end of the first week.
Stabilization Phase

Patient Management

Pharmacotherapy alone is rarely sufficient treatment for substance use disorders. Treatment outcome literature demonstrates that adding psychosocial treatment to buprenorphine treatment is correlated with better patient outcomes.

Physicians considering making buprenorphine available to their patients should

	Ensure that they are capable of providing psychosocial services, either in their own practices or through referrals to reputable behavioral health practitioners in their communities 
	Consider providing office staff training in brief treatment interventions and motivational interviewing; this information could also enhance the effectiveness of treatment for other medical problems
	Be able to determine the intensity of services needed by individual patients and when those needs exceed what the physician can offer
	Work with qualified behavioral health practitioners to determine the intensity of services needed beyond the medical services
	Establish contingency plans for patients who do not follow through with referrals to psychosocial treatments

Ordering Information

TIP 40 
Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction

Three Ways to Obtain Free Copies of All TIP Products

1.	Call SAMHSAs National Clearinghouse for Alcohol and Drug Information (NCADI) at 800-729-6686, TDD (hearing impaired) 800-487-4889.
2. 	Visit NCADIs Web site at www.ncadi.samhsa.gov.
3. 	Access TIPs online at www.kap.samhsa.gov.