Knowledge Application Program 

KAP Keys 

For Physicians
 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of 

Buprenorphine in the Treatment 

of Opioid Addiction 

Based on TIP 40 

Clinical Guidelines for the 

Use of Buprenorphine 

in the 

Treatment 

of Opioid 

Addiction 

Buprenorphine 

Clinical Guide 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Substance Abuse and Mental Health Services Administration 

Center for Substance Abuse Treatment 

www.samhsa.gov 
KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

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) 

1 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 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-tosevere pain Reckitt Benckiser No 

Buprenorphine Buprenorphine

injectable(generic) 

Injectable ampules Moderate-tosevere pain Abbott Laboratories No 
Drug Interactions 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

2 

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 sedativehypnotics 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 3 

Abuse Assessment 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

•	 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., patient’s 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., patient’s understanding 

of his or her substance use problem, patient’s interest 

in treatment now, whether treatment is coerced or 

voluntary) 
Recommended Baseline Laboratory Evaluation 

of Patients Who Are Addicted to Opioids 

4 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

• 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 syphilis—Venereal Disease Research 

Laboratories (VDRL) 

• Purified protein derivative (PPD) test for tuberculosis, 

preferably with control skin tests 
Signs of Opioid Intoxication 5 

and Withdrawal 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

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 minute) 

Pulse rate below 40 per minute 

Overdose triad: apnea, coma, 

pinpoint pupils (with terminal anoxia: 

fixed and dilated pupils) 
Staging and Grading Opioid 6 

Withdrawal 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

Stage of 

Withdrawal Grade Physical Signs/Symptoms 

Early withdrawal 

(8–24 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 

(1–3 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 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

7 

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 physician’s 

expertise 

Continued on back 
KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

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 
Patient dependent 

on short-acting opioids. 

Discontinue short-acting opioids. 

Reevaluate suitability 

for induction. 

No 

Withdrawal 

symptoms present 12–24 hours 

after last dose of 

opioids? 

Yes 

Administer 4/1 mg 

buprenorphine/naloxone. 

Observe 2+ hours. 

Yes 

Day 1 dose established. 

Withdrawal 

symptoms 

relieved? 

No 

Day 1 dose established. 

Return next day for repeat 

induction attempt. 

Yes 

No 

Withdrawal 

symptoms 

relieved? 

Repeat dose up to maximum 

8/2 mg buprenorphine/naloxone 

per 24 hours. 

Manage withdrawal 

symptomatically. 

Treatment Protocols 

Induction Days 1–2: Short-Acting Opioids 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

8 
Patient dependent 

on long-acting opioids. 

Methadone: Taper to #30 mg per day. 

LAAM: Taper to #40 mg per 48-hour dose. 

Methadone: 

Withdrawal 

symptoms 24+ hours 

after last dose? 

LAAM: Withdrawal 

symptoms 48+ hours 

after last 

dose? 

No Reevaluate suitability 

for induction. 

Yes 

Day 1 dose established. 

Withdrawal 

symptoms 

relieved? 

Yes 

Administer 2 mg 

buprenorphine monotherapy. 

Observe 2+ hours. 

No 

Day 1 dose established. 

Return next day for repeat 

induction attempt. 

Yes 

No 

Withdrawal 

symptoms 

relieved? 

Repeat dose up to maximum 

8 mg per 24 hours. 

Manage withdrawal 

symptomatically. 

Treatment Protocols 

Induction Days 1–2: Long-Acting Opioids 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

9 
Patient returns to office on 

buprenorphine/naloxone.* 

Daily dose established equal 

to total buprenorphine/naloxone 

administered on previous day.† 

Withdrawal 

symptoms 

present since last 

dose? 

No 

Yes 

Administer dose equal to the total amount 

of burprenorphine/naloxone administered 

on previous day plus an additional 4/1 mg 

(maximum 12/3 mg on day 2). Observe 2+ hours. 

Daily buprenorphine/naloxone 

dose established.† 

On subsequent induction days, if the patient returns 

experiencing withdrawal symptoms, continue dose 

increases per the schedule shown above, up to a 

maximum of 32/8 mg buprenorphine/naloxone per day. 

Withdrawal 

symptoms 

relieved? 

No 

No 

Withdrawal 

symptoms 

relieved? 

Yes 

Yes 

Administer 4/1 mg 

buprenorphine/naloxone 

(maximum 16/4 mg total on day 2). 

Manage withdrawal symptomatically. 

Treatment Protocols 

Induction Day 2 Forward 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

10 

*If buprenorphine monotherapy was administered on day 1, switch to 

burpenorphine/naloxone on day 2 (for a patient who is not pregnant). 

†Dose may be increased by 2/0.5–4/1 mg increments on subsequent 

days as needed for symptom relief. Target dose is 12/3–16/4 mg 

buprenorphine/naloxone per day by the end of the first week. 
Patient receiving 

induction. 

Induction 

phase 

completed? 

No 

Yes 

Yes Continued 

illicit opioid 

use? 

No 

Yes 

No 

No 

Compulsion 

to use, cravings 

present? 

Yes Continued 

illicit opioid use 

despite maximum 

dose? 

Continue adjusting dose up to 

32/8 mg burprenorphine/ 

naloxone per day. 

Withdrawal 

symptoms 

present? 

No 

Yes 

Daily dose of buprenorphine/ 

naloxone established. 

Maintain on buprenorphine/ 

naloxone dose. Increase intensity of 

nonpharmacological interventions. 

Consider referral to opioid treatment 

program or other more intensive 

level of treatment. 

Treatment Protocols 

Stabilization Phase 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

11 
Patient Management 

KAP Keys Based on TIP 40 

Clinical Guidelines for the Use of Buprenorphine 

in the Treatment of Opioid Addiction 

12 

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 SAMHSA’s National Clearinghouse for Alcohol 

and Drug Information (NCADI) at 800-729-6686, 

TDD (hearing impaired) 800-487-4889. 

2. Visit NCADI’s Web site at www.ncadi.samhsa.gov. 

3. Access TIPs online at www.kap.samhsa.gov. 

Do not reproduce or distribute this publication for a fee 

without specific, written authorization from the Office of 

Communications, Substance Abuse and Mental Health 

Services Administration, U.S. Department of Health and 

Human Services. 

DHHS Publication No. (SMA) 05-4105 

Printed 2005