Heroin and other opioids: Management of chronic use

Michael F Weaver, MD John A Hopper, MD

UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.3 is current through August 2007; this topic was last changed on June 11, 2007. The next version of UpToDate (16.1) will be released in March 2008.

INTRODUCTION — Patients who have gone through the acute withdrawal period from heroin or other opioids have completed only the first step toward successful long-term recovery. (See "Opioid withdrawal in the emergency setting"). Long-term addiction treatment can take many forms, including abstinence-based treatment (Narcotics Anonymous, residential treatment, and aftercare) or maintenance with opioid agonists (methadone or buprenorphine), opioid antagonists (naltrexone), or heroin itself injected in a controlled setting.

Maintenance therapy often takes place in specialized centers, but the role of the primary care physician in maintenance therapy is expanding, particularly since the introduction of buprenorphine for office based treatment [1]. (See "Overview of the recognition and management of the drug abuser").

Opioid dependence is a chronic, relapsing medical illness. Long-term treatment for opioid dependence is reviewed here. An overview of opioid abuse and initial patient evaluation is discussed separately. The management of acute opioid intoxication and withdrawal are also discussed separately. (See "Heroin and other opioids: Overview and patient evaluation" and see "Opioid intoxication in adults").

CHOICES IN OPIOID ADDICTION TREATMENT — Long-term addiction treatment can take many forms, including abstinence-based treatment (Narcotics Anonymous, residential treatment, and aftercare), opioid antagonist treatment (naltrexone), or maintenance with opioid agonists (methadone or buprenorphine or heroin administered in a controlled setting).

Pharmacotherapy versus abstinence-based therapy — After a patient completes the initial withdrawal phase of opioid dependence treatment, the clinician and patient must decide what role, if any, pharmacotherapy will play in the patient's long-term treatment plan. Factors that may be considered in this decision include duration of addiction, prior treatment experience, co-morbid medical and psychiatric conditions, and patient preferences for medication treatment.

Controlled trials and meta-analyses comparing medication and placebo show the superiority of agonist pharmacotherapy in treatment retention and reduced drug use [2-4]. A limitation of these studies is that patients generally withdraw from the medication-free arm of the trial, limiting the ability to make general conclusions about abstinence based therapy. Current clinical practice suggests that abstinence based therapy is appropriate for motivated patients who voluntarily seek treatment, despite limited empirical evidence.

Many treatment programs that provide pharmacotherapy (methadone or buprenorphine) also recommend that clients participate in 12-Step self-help group meetings such as Narcotics Anonymous (NA). However, some patients may feel stigmatized by others in these groups for taking maintenance pharmacotherapy. Clients and programs may wish to seek out specific groups that view pharmacotherapy favorably, or advise clients to focus their sharing within the group on the addiction itself. Methadone Anonymous is available as an alternative program in some cities (www.methadone-anonymous.org).

Agonist versus antagonist therapy — Once a decision has been made to use pharmacotherapy for long-term addiction treatment, the choice is whether to use an opioid antagonist such as naltrexone to maintain abstinence from all opioids, or to use an opioid agonist such as methadone or buprenorphine. Maintenance pharmacotherapy with an antagonist prevents the user from experiencing beneficial effects with subsequent opioid use, and therefore helps to extinguish continued opioid use and reinforces abstinence. Opioid agonists, alternatively, suppress craving and withdrawal symptoms.

Clients who receive an opioid agonist no longer have to spend time searching for illicit heroin or attempting to obtain prescription narcotics for abuse, and can return to a productive lifestyle. Agonist therapy is not equivalent to addiction to methadone or buprenorphine. Although they are physically dependent upon methadone or buprenorphine, patients are more likely to refrain from abusing other drugs. Some patients remain on opioid maintenance for many years, while others have been tapered off agonist therapy. After discussion with a program counselor, a client may elect to undergo detoxification by very slow tapering of the dose over several months to years.

Some occupations (which may include workers involved with public safety, transport of hazardous materials, and medical professionals) require that workers be drug-free, precluding use of methadone (and buprenorphine in some situations).

NALTREXONE — Long-term opioid addiction treatment with the opioid antagonist naltrexone, available as an oral tablet, is an option that can be offered to chronic opioid abusers. However, naltrexone causes immediate withdrawal symptoms if administered prior to detoxification. Daily oral dosing or monthly intramuscular injections result in blockage of opioid effects if opioids are used. Naltrexone maintenance is most effective in highly motivated patients who are closely supervised, or when mandated through legal probation or other authorities such as a medical board requiring its use by health care practitioners in recovery from opioid dependence.

Naltrexone is also available as a subcutaneous implant that can block opioid effects for up to five months and thus provide protection against early relapse [5,6], but this formulation is not currently available in the US. An intramuscular depot formulation of naltrexone has been developed which allows for maintenance with monthly dosing. The IM depot form has been FDA approved in the US for the treatment of alcohol dependence, though is not approved for opioid dependence.

Patients who discontinue antagonist therapy and resume opioid use should be made aware of the risk of serious overdose. This may be due to loss of tolerance to opioids and a resulting misjudgment of dose at the time of relapse [7].

METHADONE MAINTENANCE THERAPY — Methadone maintenance is a method of long-term treatment of illicit opioid abuse (primarily heroin, but also abuse of illicitly obtained prescription opioids). It involves administration of a single daily dose of the long-acting opioid in a controlled setting along with provision of counseling and social services; supportive services are vital to the success of a methadone maintenance program [8].

Methadone maintenance is defined as the use of methadone for opioid dependence treatment for more than 180 days (methadone treatment for less than 180 days is considered detoxification, not maintenance [9]). Some patients may elect to undergo detoxification by supervised very slow tapering, while others remain on a stable dose indefinitely. Patients who completely detoxify are at risk of serious overdose should they resume their former drug use. One small study found that recovering addicts who had completely detoxified from opioids were at increased risk of death from a drug overdose over the next year compared with those who did not complete detoxification [7].

Clients on a stable methadone dose can safely operate machinery and drive without significant impairment [10].

Effectiveness — Virtually all studies of the efficacy of methadone maintenance therapy have yielded positive results [2,11,12], although in one study over 50 percent of patients continued to use heroin while in a maintenance program [12]. Methadone maintenance reduces and often eliminates use of nonprescribed opioids [13,14], decreases criminal activity associated with illicit drug use [15], and reduces the spread of HIV [16-18]. Overall results are similar to those seen with long-term therapy of most chronic diseases: one-third of patients do well, one-third have fluctuating improvement, and one-third show no significant improvement [19].

Regulations in the United States — Similar to other Schedule II medications, methadone can be prescribed in the United States (US) for treatment of acute or chronic pain by any physician with a Drug Enforcement Administration (DEA) license. However, prescribing methadone for withdrawal or long-term treatment of drug dependence requires a special state and federal license [9]. It may only be used for chronic addiction by a licensed opioid treatment program or licensed inpatient hospital detoxification unit, which are required to provide counseling and social services as well as dispense methadone. Methadone maintenance clinics also provide referral for primary medical services [20]. State laws, in addition to federal laws, may mandate additional requirements or restrictions on programs.

To be eligible for methadone maintenance, a prospective client must have: physical dependence on opioids for at least one year of continuous use or intermittent use spanning a longer period of time; physical signs of opioid withdrawal, or findings of chronic use on physical examination (such as needle tracks on the skin). Criteria are also met if the client was just released from incarceration and had met criteria for physical dependence prior to incarceration. Clients who have been incarcerated for long periods and no longer have physical withdrawal are also eligible if the program physician documents a high likelihood of relapse to opioid dependence.

Clients who have been on methadone maintenance within the past two years do not need to demonstrate current physical dependence if the program physician documents an imminent return to opioid dependence. Pregnant women are eligible for methadone maintenance even if dependent for less than one year, or if they were dependent on opioids in the past and a return to dependence is likely during pregnancy.

Methadone maintenance clients must be at least 18 years old; younger clients can be admitted if they have current physical dependence and have had two previous attempts at detoxification or drug-free substance abuse treatment. Consent of a parent, guardian, or designated responsible adult is required for clients under age 18.

Dosing — A variety of methadone doses have been used for maintenance [19]. Methadone is given in doses sufficiently high that additional doses of opioid do not cause euphoria. Clients appear to do better on higher (80 to 100 mg/day) rather than lower methadone doses [21-23]; doses at these levels are not overly sedating due to the development of tolerance. Methadone inducation should involve careful initiation procedures with ongoing monitoring, limited use of take-home doses, and caution in patients who are also using benzodiazepines [24-26].

A study of 222 heroin-addicted patients seeking treatment in a VA setting, and followed for one year, found a wide range in methadone doses (1.5 to 191.2 mg, median 69 mg) were needed to achieve abstinence of at least one month [27]. Higher methadone doses were necessary in patients with depression or other psychiatric comorbidities, a greater number of previous heroin detoxifications, or living in areas where heroin was likely to be less pure.

Pregnancy — Methadone maintenance is the treatment of choice for opioid-dependent pregnant women [28]. A stable methadone dose reduces fluctuations in maternal opioid levels, which reduces stress on the fetus. Illicitly purchased heroin is adulterated with other compounds that may be harmful to the fetus, and methadone use in pregnancy reduces the risk of fetal harm from exposure to such adulterants. (See "Substance abuse in pregnancy"). Methadone maintenance also enhances the ability of the woman to participate in prenatal care and addiction treatment [29]. Methadone dose requirements may increase during the third trimester due to larger plasma volume, reduced protein binding, increased tissue binding, and increased metabolism. Splitting the total daily methadone requirement into a morning and evening dose is preferred [30,31]. Women can breastfeed on methadone as long as they are not abusing drugs and are not HIV infected [32,33].

Hospitalization — If a methadone maintenance client is hospitalized, such as for a traumatic injury or medical illness, the maintenance dose should be continued throughout hospitalization. The hospital physician should contact the methadone maintenance program to verify the client's current dose and arrange for dosing to resume after discharge. Acutely ill or injured hospital patients often experience pain; methadone maintenance clients experience the same pain despite being on methadone, since methadone reaches steady state levels in the body and does not provide additional analgesia.

Methadone maintenance patients with acute pain should be treated for pain with opioid or nonopioid medications, as would be appropriate if they were not on methadone. Recommendations for selecting, dosing, and administering pain medications follow [34]:

• Higher than usual opioid analgesic doses may be required because of opioid cross tolerance, and the patient's increased pain sensitivity.

• The patient's usual methadone dose should be continued, and short-acting opioid analgesics administered additionally. These should be given on a schedule, and not ordered as-needed.

• If the patient cannot take oral medication, methadone can be given by the intramuscular or subcutaneous route. The parenteral dose should be given as half to two-thirds the maintenance dose, divided into two to four equal doses through the day.

• Mixed agonist and antagonist opioid analgesics, such as pentazocine (Talwin), nalbuphine (Nubain), and butorphanol (Stadol) should not be administered, as they may displace methadone from the mu receptor and precipitate acute withdrawal.

• Combination products with fixed doses of acetaminophen and an opioid (such as Percocet) should be avoided for most patients, since higher opioid dose requirements may expose patients to potentially hepatotoxic doses of acetaminophen.

Side effects — Side effects of chronic methadone therapy include constipation, mild drowsiness, reduced libido and sexual performance, excess sweating, and peripheral edema [35,36]. These are typical side effects seen with long-term opioid use, whether for treatment of chronic non-malignant pain, or for illicit use.

Prolonged QTc and arrhythmia — Methadone use can prolong the QT interval, especially when used in conjunction with inhibitors of cytochrome P450, hypokalemia, or abnormal liver function studies [37]. In a series of 167 hospitalized methadone maintenance patients, 16 percent had a prolonged QT (>0.5 seconds) and 3.6 percent had torsade de pointes, compared to 0 percent of 80 control patients (injection drug users not taking methadone). A dose relationship has been observed between methadone and QT interval [37,38]. In one study, 26 of the 27 methadone users with prolonged QT were taking methadone doses >40 mg/day [37]. Torsade de pointes has also been reported with very high doses of methadone in outpatient settings, occurring in a small number of patients who had risk factors for arrhythmias [39,40].

EKG screening may be appropriate for patients taking high doses of methadone, as well as those with other risk factors for a prolonged QT (left ventricular dysfunction, hypokalemia, cytochrome P450 inhibitors, or other drugs which prolong the QT interval). (See "Acquired long QT syndrome").

Hyperalgesia — Chronic use of methadone, and other opioid agonists may result in an increased sensitivity to pain, and may develop within one month of initiating chronic opioid therapy [41-43]. The development of hyperalgesia may be a significant disadvantage to the use of methadone for opioid dependent patients with chronic pain. In one study of patients in methadone treatment programs, chronic severe pain was reported in 37 percent, and 65 percent of those with pain experienced significant impact on physical and psychosocial functioning [43]. The intensity of pain experienced by this group will be greater than in other populations, and highlights the need for aggressive and comprehensive pain management [44].

Methadone abuse — Some abuse of methadone may be related to diversion from drug treatment programs, especially outside the US. One study in the UK found that 25 percent of methadone prescriptions for maintenance use were dispensed to be taken in a non-observed setting, increasing the risk for diversion [45]. Eligibility requirements for take-home doses in the US are fairly strict, to limit diversion risk. In the US, black market distribution of tablets prescribed for chronic pain is more widespread rather than of liquid; tablets are more readily available and can be more reliably identified for content and dose by prospective black market buyers.

Overdose — There are no United States national figures for methadone-related deaths or overdoses, but a review of published studies on methadone deaths from 17 states showed a rising rate of methadone-related deaths, as well as total drug-related deaths [46]. The increase in methadone-related deaths is related to increased availability of solid tablets used for treatment of pain [47]. Similarly, a rise in methadone-related deaths in Australia was traced to increased availability of methadone for treatment of chronic pain [48].

Death during induction into methadone maintenance treatment has been reported in a series of cases from New South Wales Australia in 1994 and 1996 [24,49]. The overall mortality rate during methadone maintenance induction was 7.1 deaths per 10,000 inductions [49]. Benzodiazepines were significantly more likely to contribute to death both in methadone maintenance patients and in patients taking methadone for chronic pain [25].

Deaths related to methadone in 19 US cities exceed those due to hydrocodone or oxycodone, but fewer than those related to benzodiazepines [50]. There were 167 deaths related to methadone use in Britain in 2003; this represents an annual death rate of 112 deaths per million methadone prescriptions, contrasted with 30 deaths per million prescriptions for tricyclic antidepressant overdose [45].

Studies of methadone maintenance treatment itself demonstrate reduced mortality rates [51], with a 70 percent reduction in the risk of mortality (especially due to heroin overdose) comparing clients on methadone maintenance with untreated heroin abusers [52].

BUPRENORPHINE — Buprenorphine, a partial opioid agonist, reduces illicit opioid use with long-term therapy [3,4,22]. Buprenorphine is taken sublingually. It is available alone (brand name Subutex) or in a combination preparation (brand name Suboxone) with naloxone, an opioid antagonist that has poor oral absorption. The rationale for combination therapy is that naloxone will have little to no activity when administered sublingually, but it should discourage intravenous buprenorphine abuse since it will cause withdrawal when given parenterally [53].

A study comparing buprenorphine (maximum daily dose 8 mg sublingual) with methadone maintenance (up to 80 mg) found that more patients receiving methadone continued therapy [54]. However, of patients who completed the study, those taking buprenorphine had significantly lower rates of illicit opioid consumption. Similar results have been reported by others, suggesting that maintenance with this agent may be most useful in highly motivated patients [55]. It is also possible that the 8 mg dose of buprenorphine in these studies was inadequate. A meta-analysis concluded that buprenorphine is an effective maintenance treatment, but it is not more effective than methadone at adequate doses [3].

Buprenorphine may be safer than methadone when considered from a potential abuse perspective [45]. Doses of methadone used for opiate abuse treatment exceed the lethal dose (50 mg) for opioid-naive adults. Buprenorphine has a lower potential for causing respiratory depression than methadone, and the typical treatment dose (16 to 32 mg) can be tolerated by opioid-naive users. In contrast to methadone, however, buprenorphine does have the potential to be used as an injectable agent. Increasing use of buprenorphine for addiction treatment in France has been associated with a reduction in mortality [56].

A randomized, controlled trial (n = 40) found that significantly more patients continued therapy for one year with 16 mg of buprenorphine than with placebo (75 versus 0 percent); among the patients who continued treatment, about 75 percent of urine drug screens were negative for illicit substances [4]. In a four-week randomized study of office-based therapy, rates of negative urine screens for opioids were lower but still significantly better than placebo; patients who received buprenorphine (16 mg), buprenorphine/naloxone (16 mg/4 mg), or placebo had rates of negative urine screens of 20.8, 17.8, and 5.8 percent, respectively [57]. An open label portion of the study used buprenorphine/naloxone in doses up to 24 mg/6 mg per day and found rates of negative urine screens for opioids that ranged from 35.2 to 67.4 percent.

In the United States, buprenorphine is the first drug that can be prescribed in a physician's office for opioid detoxification and maintenance. It is classified as a schedule III controlled substance by the FDA and DEA, unlike methadone and LAAM (see "Levo-alpha- acetylmethadole (LAAM)" below), which are schedule II. Buprenorphine may only be used by certified and specially trained physicians who have registered with the Center for Substance Abuse Treatment (CSAT) of the Substance Abuse and Mental Health Services Administration (SAMHSA). Information on the training and registration process is available at buprenorphine.samhsa.gov.

The effectiveness of office-based treatment in an unselected urban population was demonstrated in a short-term study of a cohort of 99 consecutive patients treated in a hospital-based primary care practice or a freestanding neighborhood clinic [58]. The overall "sobriety" rate at six months was 54 percent and correlated with private insurance, older age, and attending self-help groups, but did not correlate with site of care or dose of buprenorphine-naloxone. "Sobriety" in this study was determined by routine unwitnessed urine samples at scheduled visits, and does not meet reference standards for sobriety (unscheduled observed drug testing over two years) which would be impractical in a community-based setting.

Physicians providing office-based buprenorphine are required to refer patients for counseling. Brief focused weekly counseling was found to be as effective as more intense three times weekly counseling in a randomized trial of patients with heroin or prescription opioid addiction receiving buprenorphine/naloxone [59]. Another study demonstrated overall high patient satisfaction with buprenorphine/naloxone in a primary care setting, especially among women and non-White patients; patients with fewer medication dispensing requirement (weekly compared to thrice weekly) had greater satisfaction [60].

Analogous to the requirements for initiating treatment with methadone in a licensed clinic, determination if a patient is appropriate for office-based opioid addiction treatment with buprenorphine begins with establishment of the diagnosis of opioid dependence. Comorbid medical and psychiatric conditions help guide the decision to treat in an office setting. The final decision depends upon whether the office has the resources available to address the individual patient's needs.

Stepped care — Arguments have been made both to routinely use buprenorphine/naloxone in lieu of methadone for greater safety, and to maintain methadone as the gold standard because it is more effective in most studies. A stepped care approach to treatment of opioid addiction, that addresses both of these concerns, has been evaluated in Sweden [61]. In a randomized controlled trial, 96 self-referred patients with heroin dependence were assigned to initial treatment either with buprenorphine/naloxone (16 mg at day 3) or methadone (titrated to 70 mg by day 10), in addition to ongoing intensive behavioral treatment. As needed, buprenorphine was titrated at two week intervals to a maximum of 32 mg daily, and methadone in 10 mg increments to a maximum of 120 mg/day. Subjects who remained symptomatic with 32 mg of buprenorphine were switched to methadone 50 mg and further titrated with methadone. Overall treatment success was excellent (retention rate in program 78 percent at 6 months) and identical for both groups; 46 percent of those who were initially treated with stepped therapy were maintained on buprenorphine. Factors, including age, gender, duration of addiction, and baseline Addiction Severity Index ratings, could not predict subjects who would remain on buprenorphine and who would require methadone treatment.

Hospitalization and acute pain management — As with methadone maintenance, patients taking buprenorphine who develop acute pain should be treated with appropriate pain medications. As with methadone patients, short acting opiates should be dosed in higher than usual doses, on a set schedule, and mixed agonist/antagonist opioid analgesics avoided (see "Hospitalization" above).

Acute pain management of patients maintained on buprenorphine is complicated by the high affinity of buprenorphine for the mu receptor. Potential competition between buprenorphine and full agonist opioids when both are administered concurrently places the patient at risk of opioid overdose when the antagonist is displaced. The rate of displacement of buprenorphine from the receptor is variable. Options for management of acute pain in buprenorphine-treated patients follow [34]:

• Continue the patient's usual dose for buprenorphine maintenance, titrate a short-acting opioid analgesic, have naloxone available, and monitor level of consciousness and respiration. Avoid abrupt discontinuation of the buprenorphine.

• Divide the daily dose of buprenorphine and administer it every six to eight hours, to maximize its analgesic effectiveness, and use additional short-acting opioid analgesia as needed.

• Discontinue buprenorphine and give full opioid analgesia (ie, sustained-release and intermediate release morphine). Resume buprenorphine maintenance with an induction period when pain is resolved.

• For hospitalized patients, discontinue buprenorphine and give methadone 20 to 40 mg daily, with a short-acting opioid analgesic to treat pain. Keep naloxone available at bedside. When pain is resolved, discontinue methadone and resume buprenorphine with an induction period.

Abuse and overdose — Buprenorphine-related deaths in patients on maintenance therapy have occurred primarily in combination with other substances, especially benzodiazepines and alcohol [62] or with intravenous abuse [63].

LEVO-ALPHA- ACETYLMETHADOLE (LAAM) — An alternative to methadone maintenance, levo-alpha-acetylmethadole (LAAM, trade name Orlaam), is a longer-acting opioid agonist that has potential serious side effects due to arrhythmias with QT prolongation [64]. LAAM has been withdrawn from the European market, and is no longer manufactured in the United States. EKG monitoring and special licensing are required for its use.

When available, LAAM may be considered for clients who have failed treatment with methadone and may possibly be more effective than high-dose methadone for reducing illicit opioid use [22,65,66].

HEROIN MAINTENANCE PROGRAMS — Several countries (including Switzerland and the Netherlands) have instituted programs which include provision of injectable heroin prescriptions to addicts who have failed other maintenance therapy [67-69]. Canada has initiated a heroin prescription program for injection drug users in Vancouver. The Swiss program has demonstrated a reduction in the risk of infection with hepatitis B and C viruses [70], decrease in the incidence of heroin use, and early entry (within two years) of users into methadone substitution programs [68]. It is hypothesized that the "medicalization" of heroin use has made it less attractive for young people. One Dutch study suggested a cost utility benefit for heroin co-prescription in treatment-resistant heroin users, with program costs offset by lower estimated costs for law enforcement and damage to victims of crime [71].

There is considerable controversy regarding this approach to managing opiate addiction. Reports of outcomes from these programs are not based on randomized studies, and are not necessarily applicable to other populations. The longterm consequences of potential drug substitutions, drug diversions, coaddictions, and other risks of prescription heroin injection programs need to be explored, and weighed against potential benefits, from both the societal and individual drug-user perspective.

SUMMARY AND RECOMMENDATIONS

• Further treatment is indicated for patients who have completed acute withdrawal from heroin or other opioids. Treatment may entail participation in hospital or community-based drug programs, participation in support programs such as Narcotics Anonymous, long-term maintenance with opioids or opioid antagonists, or transition to drug abstinence. (See "Introduction" above).

• Methadone maintenance therapy, in the context of a social support program, is beneficial for program participants, allowing them to return to normal life activities, and decreasing risk of infection. Most clients do best on methadone doses around 80 to 100 mg/day, sufficient to block a euphoric response if they self-administer additional opioids. (See "Effectiveness" above and see "Dosing" above).

• Patients in methadone programs who require hospitalization for pain or surgery should be maintained on their usual methadone dose and given additional short-acting opioid analgesia on a scheduled dose. (See "Hospitalization" above).

• Naltrexone has limited use for maintenance therapy, and is most effective in highly motivated patients. It can precipitate immediate withdrawal symptoms (See "Naltrexone" above).

• Buprenorphine, a partial opioid agonist taken sublingually, provides effective maintenance therapy for motivated patients, and can be prescribed in the US in a physician's office by specially trained physicians. Management of hospitalized patients requiring medication for acute pain, who are maintained on buprenorphine, is complicated by risk of opioid overdose and care should be taken in patient management. (See "Hospitalization and acute pain management" above).

• Parenteral heroin administration has been effective in treatment-resistant patients in nonrandomized studies of European programs; concerns remain about risks and benefits (See "Heroin maintenance programs" above).

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