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Center for Substance Abuse Treatment. Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Programs. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2005. (Treatment Improvement Protocol (TIP) Series, No. 43.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Programs.

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Chapter 11. Treatment of Multiple Substance Use

In This Chapter …

Prevalence of Multiple Substance Use in MAT

Common Drug Combinations Used by Patients in MAT

Effects of Other Substance Use

Management of Multiple Substance Use in MAT

Inpatient Detoxification and Short-Term Stabilization

Concurrent opioid and other substance use is a serious problem in opioid treatment programs (OTPs). Patients in medication-assisted treatment for opioid addiction (MAT) commonly use alcohol, amphetamines, benzodiazepines and other prescription sedatives, cocaine, and marijuana (THC [delta-9-tetrahydrocannabinol]). Patterns of use range from occasional low doses to regular high doses that meet dependence criteria. Central nervous system (CNS) depressants such as alcohol, benzodiazepines, and barbiturates are especially dangerous when used with opioids.

Except for naltrexone, which is used to treat alcohol dependence, the treatment medications used in MAT do not address nonopioid substance use directly, although patients stabilized on adequate treatment medication are less likely to abuse other substances than patients who are undermedicated. Because multiple substance use during MAT may complicate treatment greatly, the consensus panel recommends that staff members be trained to recognize the pharmacologic and psychosocial effects of both opioid and nonopioid substances of abuse. OTPs should have treatment options available to address multiple substance use either directly or by referral.

An essential purpose of preliminary assessment is to determine whether new patients are abusing or are dependent on substances other than opioids (see chapter 4). If one of these problems is identified, OTPs should adjust treatment plans and the types of services provided accordingly. OTPs should not exclude patients automatically from MAT who test positive for illicit drugs other than opioids. Treatment providers should treat patients for their concurrent substance abuse aggressively or refer them appropriately. Providers should try to understand and address the underlying causes of concurrent substance use.

Prevalence of Multiple Substance Use in MAT

Patients Entering OTPs Who Abuse Other Substances

The Treatment Episode Data Set (TEDS) summarizes data on admissions to substance abuse treatment programs in the United States. According to TEDS, 42.7 percent of patients entering substance abuse treatment in OTPs in 2000 reported using only heroin (Substance Abuse and Mental Health Services Administration 2002d ). Exhibit 11-1 presents TEDS data on heroin and other substances used by people admitted to OTPs in 2000. Proportions of patients using additional drugs and the types of drugs used varied by locality, depending primarily on drug availability. Although not shown in Exhibit 11-1, rates of cigarette smoking in this population reportedly range from 85 to 92 percent (Clarke, J.G., et al. 2001; Clemmey et al. 1997).

Exhibit 11-1. Reported Use of Other Substances by Patients Admitted to OTPs

Primary Substance of Abuse
Heroin Other Opioids
Total number of admissions243,52325,839
Average number of substances used (per admission)1.81.8
Substance Used in Addition to Primary Substance Percent Percent
Nonsmoked cocaine22.27.2
Smoked cocaine12.15.4
Other stimulants0.20.3
Other opioids4.31.3

Percentages sum to more than 100 because 1 patient could report more than 1 additional substance.

NA, not applicable.

Exhibit 11-2 summarizes results of a large-scale study of co-dependence in 716 patients admitted to OTPs in Baltimore, Maryland, over a 5-year period (1989 to 1994). Patients with co-occurring disorders had higher rates of substance co-dependence than patients without co-occurring disorders. Rates were substantially higher for lifetime co-dependence, even among patients not co-dependent during the study (Brooner et al. 1997).

Exhibit 11-2. Current Substance Use Disorders in Patients Dependent on Another Substance While Addicted to Opioids and Admitted to OTPs, With and Without Co-Occurring Disorders (N=716)

SubstanceWith Co-Occurring Disorders (%)Without Co-Occurring Disorders (%)

Percentages sum to more than 100 because 1 patient could report more than 1 additional substance.

Adapted from Brooner et al. 1997.

Emergency Room Admissions and Fatalities Involving Concurrent Opioid and Other Substance Use

The Drug Abuse Warning Network tracks data from hospital emergency departments and other institutions that report admissions for substance use and drug-related deaths. In 2001, 93,064 nonfatal admissions mentioned heroin use. Of these, 5 percent mentioned concurrent alcohol use only, 25 percent mentioned concurrent use of another drug but not alcohol, and 15 percent mentioned concurrent use of alcohol and another drug or other drugs as well as heroin (Substance Abuse and Mental Health Services Administration n.d.a ). Nearly 90 percent of heroin-related deaths may involve concurrent use of other substances (Substance Abuse and Mental Health Services Administration 2002b ).

Common Drug Combinations Used by Patients in MAT

Exhibit 11-3 summarizes reasons patients in MAT give for using particular combinations of substances, based on the consensus panel's experience. A common reason is that patients have become dependent on the substance along with their opioid addiction. Another common reason is the need to self-medicate withdrawal symptoms or uncomfortable affects (e.g., anxiety, depression, anger, loneliness) related to non—substance-induced mental disorders or difficult life situations. Patients' initial substance use experiences and continued attraction to drugs may indicate enhancement—avoidance reactions. That is, substances may be used to enhance an experience (e.g., use of alcohol as a social lubricant or cocaine to heighten sexual pleasure) or to avoid or neutralize strong feelings (e.g., incest survivors' substance use before sex to numb their feelings or adolescents' substance use before sex to avoid accepting responsibility for their actions). Some patients develop unique drug regimens that vary throughout the day, for example, using stimulants in the morning, anxiolytics in the afternoon, and hypnotics at night.

Exhibit 11-3. Drug Combinations and Common Reasons for Use

Heroin plus alcoholEnhance a high; create euphoria or sedation
Heroin followed by alcoholMedicate opioid withdrawal; medicate cocaine overstimulation (e.g., anxiety, paranoia)
Heroin plus cocaine (“speedball”)Enhance or alter cocaine euphoria
Heroin followed by cocaineMedicate opioid withdrawal
Cocaine plus alcoholEnhance high; reduce cocaine overstimulation (e.g., anxiety, paranoia)
Cocaine followed by heroinReduce cocaine overstimulation (e.g., anxiety, paranoia); modulate the cocaine crash
Methadone plus alcoholCreate a high; sedate
Methadone plus cocaineReduce cocaine overstimulation (e.g., anxiety, paranoia); moderate the cocaine “crash”
Methadone plus benzodiazepinesCreate a high; sedate
Any opioid plus any nonbenzodiazepine sedativeCreate a high; sedate
Any opioid followed by any nonbenzodiazepine sedativeMedicate opioid withdrawal
Any opioid plus amphetamineCreate a high

Effects of Other Substance Use


The acute effects of alcohol are well known, including sedation, as well as impairment of judgment, coordination, psychomotor activity, reaction time, and night vision. Overdose deaths can occur when alcohol is used alone in high doses or in lower doses with opioid treatment medication or sedatives (Hardman et al. 1996). The effects of concomitant alcohol and methadone, levo-alpha acetyl methadol (LAAM), or buprenorphine use are additive and more sedating than either alcohol or treatment medication alone. Alcohol abuse can aggravate liver damage from hepatitis C, which is common among patients in MAT. Alcohol-related factors are a major cause of death among patients in MAT, both during and after treatment, and of administrative discharges from OTPs (Appel et al. 2000). On average, patients in MAT who are alcohol dependent have more medical and mental disorders, greater criminality, and poorer social and family functioning and peer relations than patients who are not alcohol dependent (Chatham et al. 1995b ).

Alcohol abuse among patients in MAT can affect treatment compliance (Bickel and Amass 1993) and outcomes adversely. Continuous use may induce enzyme activity that increases the metabolism of treatment medication, reducing medication plasma levels and resulting in symptoms of undermedication that further complicate treatment.

Research is limited or conflicting on alcohol disorder treatment for patients in MAT. Many studies comparing alcohol use before OTP admission and after 1 year have found little or no improvement (e.g., Fairbank et al. 1993; Hubbard et al. 1997). However, one study found that short-term MAT reduced alcohol consumption significantly in patients who did not meet alcohol-dependence criteria (Caputo et al. 2002), and a 10-year study found that less than 6 percent of patients in MAT reported alcohol problems in the previous 6 months (Appel et al. 2001).

Lubrano and colleagues (2002) found an association between inadequate methadone doses and increased cravings for both heroin and alcohol. Others noted that continued alcohol consumption among patients dependent on alcohol was associated with smaller increases in methadone doses during MAT (El-Bassel et al. 1993). Stastny and Potter (1991) found that many patients in MAT who abused alcohol also abused benzodiazepines.

Treatment for alcohol dependence involves a comprehensive approach combining detoxification if needed, counseling, medications such as disulfiram, and participation in mutual-help groups (Fuller and Hiller-Sturmhofel 1999). Many groups do not support use of maintenance medication. Other interventions have met with limited success. A pilot study provided intensive education for staff members at OTPs in which 220 patients receiving methadone also were treated for alcohol dependence. Eighty percent of these patients complied with treatment requirements and completed treatment (Kipnis et al. 2001).


Benzodiazepines such as diazepam (Valium®) and clonazepam (Klonopin®) have antianxiety and sedative effects. They are schedule IV drugs, signifying relatively low abuse liability. However, people with other addiction disorders are more likely to abuse benzodiazepines than are members of the general population (Ross and Darke 2000). In an early study, patients receiving opioid treatment medication who also abused benzodiazepines typically took the latter within 1 hour of the former and reported that benzodiazepines increased the effects of the medication (Stitzer et al. 1981). These effects likely result from an interaction in which each drug potentiates the sedative aspects of the other—known on the street as “boosting.” When used in prescribed doses, benzodiazepines are not dangerous for patients in MAT, except when they cause patients to seek other drugs with sedative effects. High-dose benzodiazepines can cause serious problems, including severe intoxication and higher risk of injuries or fatal overdoses. These risks are potentiated when high doses of benzodiazepines are mixed with methadone or other drugs that produce sedation and respiratory depression, even among patients in MAT who have developed tolerance for the respiratory-depressant effects of opioids.

In the experience of the consensus panel, patient use of benzodiazepines negatively affects attendance at treatment sessions and progress in MAT. Regular benzodiazepine use for 3 months or more may be associated with physiologic dependence, even when benzodiazepines are taken in prescribed doses. Patients who are abusing or dependent on benzodiazepines usually need detoxification and more intensive treatment interventions to remain safely in MAT.

Nonbenzodiazepine Sedatives

Nonbenzodiazepine sedatives such as intermediate- or short-acting barbiturates or glutethimide are more likely than benzodiazepines to produce lethal overdose because people who abuse them develop tolerance for their sedative and euphoric effects but not for their respiratory-depressant effects. Therefore, as these people increase their dosages to get high, they suddenly can overdose to respiratory depression. People who are opioid addicted and abuse nonbenzodiazepine sedatives usually need inpatient detoxification before starting MAT or may do better with referral to a long-term, residential program such as a therapeutic community. Nonbenzodiazepine sedatives induce cytochrome P450 3A, an enzyme involved in methadone, LAAM, and buprenorphine metabolism (see chapter 3), and can make stabilization difficult.

The consensus panel recommends that OTPs withhold treatment medication for patients who appear intoxicated with a sedative-type drug until intoxication has cleared and patients are either detoxified from sedatives or confirmed not to be sedative dependent. Nonbenzodiazepine sedative and barbiturate abuse is rare in most areas. These medications are less widely abused than in the past, because benzodiazepines are less dangerous and easier to obtain in many areas.

Cocaine and Other Stimulants

Stimulant abuse, especially cocaine, is another serious problem in many OTPs (see Exhibit 11-1). Adverse effects of these substances include cardiovascular effects (hypertension, stroke, arrhythmias, myocardial infarction), respiratory effects (perforation of nasal septum, bronchial irritation) if inhaled or smoked, or mental effects (anxiety, depression, anger, paranoia, psychotic symptoms). Patients in MAT who abuse stimulants may be disruptive if the stimulants have severe mental effects, and these patients may have problems with mood swings and compliance with group or individual therapy. TIP 33, Treatment for Stimulant Use Disorders (CSAT 1999c ), provides more information.

Another concern for patients in MAT who use cocaine is concurrent alcohol use. The combination of alcohol and cocaine is popular because it can create a more intense high and less intense feelings of inebriation than either substance alone. Individuals also use alcohol to temper discomfort when they come down from a cocaine-induced high. Patients in MAT who abuse both alcohol and cocaine are significantly more difficult to engage and retain in treatment than patients who do not abuse all three substances (Rowan-Szal et al. 2000b ). In addition, cocaethylene, a psychoactive derivative of cocaine formed exclusively during the combined administration of cocaine and alcohol, can increase the cardiotoxic effects of either substance alone. The combination of alcohol and cocaine tends to have exponential effects on heart rate and may increase violent thoughts and tendencies (Pennings et al. 2002). The mixture of opioids, cocaine, and alcohol can be lethal and has been identified as a leading cause of accidental overdose (Coffin et al. 2003).

Tennant and Shannon (1995) found that cocaine use appeared to lower the methadone concentration in blood. In addition, some patients reduced their cocaine use when their methadone dosages were increased. Borg and colleagues (1999) found that adequate doses of methadone seemed to reduce cocaine use even though methadone does not target cocaine directly. More focused treatments and research on these interactions are needed.

Traditionally, disulfiram has been used to treat alcohol dependence (chapter 3). Because cocaine often is used with alcohol, Petrakis and colleagues (2000) evaluated disulfiram treatment for cocaine dependence, with and without alcohol abuse, for patients in MAT. Patients who were treated with disulfiram significantly decreased the quantity and frequency of their cocaine use, whereas those treated with a placebo did not. Related studies found that the positive effects of disulfiram on cocaine use among patients in substance abuse treatment remained evident after 1 year (Carroll et al. 2000) and that disulfiram also was promising for patients treated with buprenorphine (George et al. 2000). More research on the benefits of disulfiram therapy for cocaine dependence during MAT is needed.


In general, THC use is not as prevalent as cocaine or amphetamine use among patients in MAT (see Exhibit 11-2). Some studies have concluded that THC use in MAT does not affect MAT outcomes adversely. For example, Epstein and Preston (2003) found that THC was not associated with either poor treatment retention or problem use of other substances such as cocaine. One study (Wasserman et al. 1998) showed that, for patients committed to opioid abstinence and doing well, positive tests for THC could predict relapse, but this finding has not been replicated (Epstein and Preston 2003).

OTPs vary in whether they require THC-free drug tests before patients can qualify for or continue take-home medication privileges. The consensus panel recommends that OTPs address patient THC use because, as with other substances of abuse, THC increases the probability that patients will engage in activities that put them at higher risk of relapse to opioid use, other health problems, other related illicit activities, and legal problems.

Patients in MAT sometimes use THC to self-medicate for anxiety or insomnia. Approaches to address THC use in these patients include increased counseling, treatment of their anxiety disorders with standard psychotropic medications and psychotherapy, and requirements that drug tests be free of THC before patients can qualify for take-home medication. Unlike people addicted to nonopioid substances, patients in MAT who are opioid addicted rarely seek treatment for THC dependence. Therefore, it has received less attention in OTPs than in other substance abuse treatment programs.


Tobacco—smoking-related illnesses are a major cause of morbidity and mortality among patients in MAT as they are in the general population. For example, 40 percent of deaths over 15 years in one physician's office-based MAT program were related to cigarette smoking, which was more than deaths from HIV/AIDS, hepatitis C, and violence combined (Salsitz et al. 2000). Frosch and colleagues (2000) found that patients in MAT who smoked heavily were more likely to abuse cocaine and opioids than were patients who did not smoke heavily, suggesting an association between nicotine and other substance use. In other research, patients receiving methadone who reduced their tobacco use also reduced cocaine use, although cocaine was not addressed directly in treatment (Shoptaw et al. 1996).

Many OTPs avoid addressing nicotine dependence because it may create additional stress for patients. Research has shown that smoking interventions neither detract from nor interfere with addiction recovery and that patients who attempt nicotine cessation are at the same risk for relapse as other patients (Ellingstad et al. 1999; Hughes 1995). Furthermore, many patients in MAT want to stop smoking (Clemmey et al. 1997).

The consensus panel believes that OTPs should address nicotine dependence routinely. In addition, because effective medications are available, tobacco cessation should be a regular part of patients' treatment plans. The forthcoming TIP Detoxification and Substance Abuse Treatment (CSAT forthcoming a ) contains information on medications and other interventions for nicotine cessation.

Management of Multiple Substance Use in MAT

Although some studies have indicated that patients in MAT reduce other substance use significantly when they receive adequate doses of methadone, LAAM, or buprenorphine, none of these medications reliably and consistently stopped nonopioid abuse in studies reported by Borg and colleagues (1999) and by Tennant and Shannon (1995). A major concern is how to determine what level of other substance abuse by patients indicates that MAT is insufficient and other treatments should be tried or that MAT should be stopped, perhaps against patient wishes.

Some have argued for early treatment discharge if patients continue using multiple substances. In addition, some State regulations set specific timetables for compliance, although the requirement is unsupported by research. Some OTP staff members may feel that patients' continued use of alcohol and illicit drugs, despite progress in recovery from opioid addiction, reflects negatively on OTP credibility and that these patients are taking the places of people who would benefit more from MAT. Patients who continue using illicit drugs sometimes erode the morale of other patients, who may conclude that treatment compliance and abstinence are optional.

Policies favoring treatment termination for patients who use substances negate a fundamental principle—that longer retention in treatment is correlated highly with increased treatment success (Hubbard et al. 1997, 2003). In fact, substantial remission from all substance use is a common and positive outcome of MAT, particularly when treatment includes regular drug counseling and other psychosocial services (McLellan et al. 1993). Consensus panel members have found that, if patients with secondary substance use problems remain in MAT and staff members address overall substance abuse patterns for these patients, many patients stop using nonopioid and nonprescribed substances.

Changing staff attitudes can be helpful to both patients and staff. Abuse of other substances along with opioid addiction presents many problems and challenges for treatment providers and patients. Without treatment, a person with these problems may continue criminal activity; remain obsessed with substance use; experience severe financial, vocational, and personal problems; and be at increased risk for overdose death.

Given the importance of retention in MAT for positive outcomes, the consensus panel agrees that a policy of discharge for other substance use is seldom appropriate. Instead of setting standard timetables for discharge, limits should be determined on a case-by-case basis. Patient discharge should be done with great caution for reasons stated elsewhere in this TIP (e.g., chapter 8) and only when staff members have exhausted all reasonable alternatives. When grappling with these difficult problems, providers should keep in mind where patients started, how far they have progressed, the degree to which they are engaged in treatment, whether all available interventions have been tried, the risk—benefit ratio of keeping these patients in treatment versus discharging them, and a realistic expectation for patients, given the resources available. If discharge must occur, staff members should work with patients to arrange transfer to another program where a treatment slot is open and they can obtain more benefit.

Other Procedures

A key element in treating multiple substance use in an OTP is the need for intensified services and heightened structure and supervision (see chapter 8). Because few chronic diseases respond to a single care model, OTPs need a variety of techniques for patients who abuse multiple substances. These techniques should incorporate available medical, mental health, and social services. Usually patients who abuse multiple substances require a more intensive level of care for a limited period. Treatment providers also should have referral agreements with inpatient facilities for brief detoxification from nonopioid substances, extended stabilization before reentry into an OTP, or admission to a therapeutic community, residential treatment, or other long-term, more structured and controlled environment. OTPs can enter into agreements with residential treatment programs to allow continued MAT along with treatment for other substance dependence.

A common problem is that some OTP staff members and patients assume that stopping opioid and injection drug use is the sole objective of treatment. Use of cocaine and other substances should cause concern because it undermines patient stability. Nonetheless, use of some substances such as THC may be viewed as less serious unless clear evidence exists of impaired functioning. Many people entering an OTP regard alcohol use as acceptable because it is legal. Changing such attitudes and behaviors requires patience and effort. OTPs should have clear policies declaring the desirability of cessation of all substance use. These policies should clarify any ambiguity about abstinence from nonprescribed medications but encourage therapeutic use of medications that are effective to treat legitimate, diagnosed conditions. OTPs should encourage abstinence from alcohol and nicotine, but it is difficult to require it because these are legal substances. However, OTPs may withhold medication if patients have consumed alcohol shortly before or are intoxicated during treatment and should address alcohol problems.

The consensus panel believes it is helpful, both when patients are admitted to an OTP and throughout treatment, to maintain the position that opioid use is only the most obvious part of patients' problems and that the role of all intoxicants (both licit and illicit) in patients' lives and their overall substance-using lifestyle are other important issues. Patients in MAT should recognize that use of any intoxicant undermines their progress.

Dosage Adjustments

During the dosing period (see chapter 5), OTPs should ensure that patients' dosages suppress withdrawal and produce significant cross-tolerance for opioids of abuse. Patients may be abusing other drugs to self-medicate withdrawal symptoms caused by inadequate dosages or other factors that affect medication metabolism. In this case, raising the dosage or splitting doses may lessen other substance use.

Increased Counseling and Other Psychosocial Services

Numerous studies have shown that regular counseling is associated with a reduction in opioid and other substance use by patients in MAT (Villano et al. 2002; see chapter 8 in this TIP). In a study of patients who abused multiple substances and had co-occurring disorders or criminal histories, those who received more intensive cognitive behavioral treatments reduced their cocaine use more than those in less intensive treatment (Rosenblum et al. 1995). In another study of patients in MAT who received additional cognitive behavioral therapy for cocaine abuse and patients who received standard methadone treatment, cocaine use declined significantly for both groups (Magura et al. 2002).

Increased Drug Testing

One obstacle to detecting other substance use during MAT is that infrequent drug tests primarily identify only those patients who use substances frequently, for example, daily. Early detection and intervention requires occasional periods of more intensive, random drug testing. OTPs, however, should have objective policies that require combining increased drug testing with more intensive counseling. Testing frequency might be used as a contingency, with more negative tests for illicit drugs resulting in less frequent testing (see chapter 8).

Inpatient Detoxification and Short-Term Stabilization

Use of alcohol or other CNS depressants with opioids may cause depression of respiration, loss of consciousness, life-threatening withdrawal reactions, and increased risk of lethal overdose (Baskin and Morgan 1997). This type of withdrawal is not treatable with methadone (Sporer 1999; White and Irvine 1999). Signs and symptoms of withdrawal from CNS depressants include elevated body temperature, hypertension, rapid pulse, confusion, hallucinations, and intractable seizures. When a patient in MAT abuses a CNS depressant, the depressant should be withdrawn medically from the patient's system, and the opioid treatment medication should be continued with consideration of the need for a dosage increase.

The patient may require inpatient detoxification from CNS depressants and should continue MAT during the inpatient stay. In addition, a history of seizures or toxic psychosis during withdrawal from a sedative-hypnotic or anxiolytic drug or from alcohol is an absolute indication for inpatient detoxification. The forthcoming TIP Detoxification and Substance Abuse Treatment (CSAT forthcoming a ) contains more information on detoxification from substances of abuse.


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