Morphine makes lasting — and surprising — change in the brain

Morphine, as little as a single dose, blocks the brain’s ability to strengthen connections at inhibitory synapses, according to new Brown University research published in Nature

The findings, uncovered in the laboratory of Brown scientist Julie Kauer, may help explain the origins of addiction in the brain. The research also supports a provocative new theory of addiction as a disease of learning and memory.

„We’ve added a new piece to the puzzle of how addictive drugs affect the brain,“ Kauer said. „We’ve shown here that morphine makes lasting changes in the brain by blocking a mechanism that’s believed to be the key to memory making. So these findings reinforce the notion that addiction is a form of pathological learning.“

Kauer, a professor in the Department of Molecular Pharmacology, Physiology and Biotechnology at Brown, is interested in how the brain stores information. Long-term potentiation, or LTP, is critical to this process.

In LTP, connections between neurons – called synapses, the major site of information exchange in the brain – become stronger after repeated stimulation. This increased synaptic strength is believed to be the cellular basis for memory.

In her experiments, Kauer found that LTP is blocked in the brains of rats given as little as a single dose of morphine. The drug’s impact was powerful: LTP continued to be blocked 24 hours later – long after the drug was out of the animal’s system.

„The persistence of the effect was stunning,“ Kauer said. „This is your brain on drugs.“

Kauer recorded the phenomenon in the ventral tegmental area, or VTA, a small section of the midbrain that is involved in the reward system that reinforces survival-boosting behaviors such as eating and sex – a reward system linked to addiction. The affected synapses, Kauer found, were those between inhibitory neurons and dopamine neurons. In a healthy brain, inhibitory cells would limit the release of dopamine, the „pleasure chemical“ that gets released by naturally rewarding experiences. Drugs of abuse, from alcohol to cocaine, also increase dopamine release.

So the net effect of morphine and other opioids, Kauer found, is that they boost the brain’s reward response. „It’s as if a brake were removed and dopamine cells start firing,“ she explained. „That activity, combined with other brain changes caused by the drugs, could increase vulnerability to addiction. The brain may, in fact, be learning to crave drugs.“

Kauer and her team not only recorded cellular changes caused by morphine but also molecular ones. In fact, the researchers pinpointed the very molecule that morphine disables – guanylate cyclase. This enzyme, or inhibitory neurons themselves, would be effective targets for drugs that prevent or treat addiction.

Pharmacist education in MMT.!, syringes,

Pharmacists have the unique knowledge, skills and responsibilities for assuming an important role in substance abuse prevention education and assistance…  Pharmacists, as health care providers, should be actively involved in reducing the negative effects that substance abuse has on society, health systems and the pharmacy profession.

— American Society of Health-System Pharmacists (2003)

Competency framework

Unless they have taken special training, most pharmacists are unaware of the clinical and practice issues surrounding methadone and their impact on client safety because they have had little or no exposure to them during their undergraduate pharmacy education.

The role of the pharmacist in MMT is unusual and there is no similar model in other therapeutic areas. Daily interactions with clients, along with direct clinical assessments, supervised dose administration and close monitoring do not usually occur in other types of pharmacy care. Pharmacists require a set of key competencies to ensure client safety in methadone maintenance treatment.

The panel recommends that:

15. Pharmacy managers/owners, hospital pharmacy directors and the Ontario College of Pharmacists support and encourage pharmacists providing methadone services to have education in and/or demonstrate knowledge and skills in core competency areas. These areas include:

a. Substance use disorders, including opioid dependence. [IV]

b. The varied models of substance abuse treatment, including harm reduction and its implications for pharmacy. [IV]

c. The impact of attitudes and stigma on client care. [III]

d. Methadone maintenance treatment clinical guidelines and their rationale, particularly with respect to practices to protect client safety, including:

• assessing initial and increased doses for appropriateness
• assessing methadone-dosing histories (for missed doses and irregularities in pattern of pickup) before dispensing a dose of methadone to a client
• ensuring the safe provision of “carries” (take-home doses) to clients
• dealing with intoxicated clients, including understanding the risks of polysubstance abuse. [IV]

Pharmacists need to understand substance use disorders, particularly addiction, and to understand the difference between “use” and “use disorders.” Pharmacists need to be able to identify individuals with substance use disorders and to help motivate them to seek change and treatment. As one of the most accessible health care professionals, the pharmacist can play an important role and refer patients to appropriate services and substance use treatment programs. Many MMT clients have concurrent substance use disorders with substances such as alcohol, benzodiazepines or cocaine. Pharmacists should understand the risks associated with polysubstance use and the risk of toxicity.

Although pharmacists may already be involved in harm reduction, for example, by providing sterile needles and syringes to people who use injection drugs, further involvement could include offering advice to people with substance use problems about health issues and how to minimize health risks. A random survey of 2,017 Canadian pharmacists by Myers et al. (1998) found that while more than 88 per cent of pharmacists were comfortable with the harm reduction role in providing needles and syringes, this comfort did not extend to providing methadone services. This may be due to a misunderstanding of the benefits of methadone maintenance treatment and its role as a harm reduction approach. Educational initiatives need to address such misunderstandings and other negative attitudes or misperceptions that may be held by pharmacists.

Pharmacists must have a good understanding of the critical safety issues associated with methadone. Methadone has a unique pharmacological profile that makes it useful in the treatment of opioid dependence; however, it is different from other opioids and the implications of its long half-life can lead to risks of accumulation contributing to methadone overdose and deaths.

The initiation phase of methadone treatment can be a time of high risk for toxicity and pharmacists’ understanding of dosing recommendations is critical at this stage. Pharmacists need to exercise particular vigilance in monitoring client dosing for appropriateness. For example, where clients have missed several doses (defined as three or more), or fewer (one or two) during periods of methadone dose escalation, pharmacists must understand the concept of loss of tolerance and risks to clients if the usual regular methadone dose is administered (CPSO, 2005).

Pharmacists also have to understand the safety issues associated with “carries.” Having a written carry agreement with the client is one way to help the client understand these issues as well. Pharmacists should be aware of some of the signs that indicate a formerly stable client on a high level of carries is relapsing to instability (e.g., missing observed dosing days, lost carries) (CPSO, 2005).

Pharmacists in Ontario need to be familiar with the CPSO’s most recent Methadone Maintenance Guidelines (2005), the OCP’s Policy for Dispensing Methadone (2006), and CAMH’s Methadone Maintenance: A Pharmacist’s Guide to Treatment (Isaac et al., 2004).

Understanding the risks of polysubstance use and knowing how to deal with intoxicated clients are particularly important core competency areas for pharmacists, with significant safety implications. The pharmacist should have an understanding of the impact that polysubstance use (for example, use of benzodiazepines, alcohol and cocaine) can have on the client taking MMT. Through dialogue and checking for signs of excessive dosing or substance use such as sedation, slurring of speech, smelling of alcohol and unsteady gait, the pharmacist should be able to assess if a client is intoxicated before dosing.

Recommendations from the coroner have highlighted the need for assessing clients for intoxication because deaths have occurred through combination of methadone and other drugs, including alcohol (OCP, 2008).

In an Australian survey (Peterson et al., 2007), pharmacists identified the risk of overdose associated with methadone alone and in combination with other psychoactive drugs as the greatest problematic issue for pharmacists in deciding to provide a methadone service.

In a survey of 148 pharmacists in Australia (Koutroulis et al., 2000), when asked about how they would respond to clients who presented intoxicated for their methadone dose, 44 per cent said they would withhold the dose and inform the client of this. This is the desirable course of action. However, 32 per cent of pharmacists said they would provide the usual dose, 16 per cent would dispense a reduced dose without the client knowing and nine per cent said they would blind the dose with a placebo. Only two per cent of the pharmacists indicated that they would breathalyse an intoxicated client.

Pharmacists who withheld the methadone dose were more likely to inform the prescriber (74 per cent) than pharmacists who dispensed the usual or modified dose. In a focus group, the reasons for dispensing to an intoxicated client were categorized as follows:

• insufficient communication between prescriber and pharmacist
• downplaying the risk of toxicity
• personal beliefs and values
• fear of what the client would do if dose refused
• difficulty in recognizing intoxication and lack of education and training.

Further, Koutroulis et al.’s survey suggested that pharmacists who had more than 10 methadone clients were more likely to provide the usual methadone dose than pharmacists with 10 or fewer clients.

Educational offerings

Many physicians and pharmacists don’t think they see addicts in their practice. The reality is they probably are treating them for other disorders, but the patient just hasn’t been identified as an addict. This also means that dependence treatment needs to become part of regular pharmacy practice as well.

— Open discussion, physicians and pharmacists (Raisch et al., 2005)

The panel recommends that:

16. All pharmacy students receive education on substance abuse, including opioid dependence, its treatment and practical intervention strategies, in their undergraduate curriculum. [IV]

Future pharmacists need to be adequately educated on substance use so that they are prepared upon graduation to care for patients with substance abuse disorders. In particular, opioid dependence and its treatment should be required components in the curriculum. Pharmacists who have had education in this area are likely to feel more comfortable providing pharmaceutical care to this group of clients.

Currently there are two faculties of pharmacy in Ontario, at the University of Toronto and at the University of Waterloo. The Waterloo faculty initiated their program in January 2009; therefore, their plans for curriculum on substance abuse education are still in the development phase.

At Toronto’s Faculty of Pharmacy, pharmacy students receive a rigorous scientific and clinical education over four years but receive little or no education on substance abuse and its treatment. Since the early 1990s, an elective fourth-year problem-based course has been offered (Busto et al., 1994). This course has one 2-hour segment on opioid abuse and treatment. It includes a didactic component, as well as an MMT client interview and discussion of stigma and attitudes. The course is elective and only a small proportion of the fourth-year class has taken this course offering.

Over the last five years enrolment in this elective has increased from 9.7 per cent of the class (13/134 students) in 2003–2004 to 34.2 per cent of the class (79/231 students) in 2008–2009 (personal communication, Dr. B. Sproule, April 29, 2009). Clearly, most future pharmacists have no exposure to substance use, opioid dependence and treatment with methadone.

The lack of specific undergraduate educational activities about substance abuse results in a missed opportunity to positively influence the knowledge, skills and attitudes of future pharmacists in this area.

As the most accessible of all health care professionals, pharmacists have an important role to play to help prevent and treat substance abuse disorders in their clients (Tommasello, 2004). Preparation for this role should begin in the undergraduate pharmacy training.

Experiential learning and other innovative teaching methods, for example, involving real patients (or simulated cases), audiovisual vignettes or other online modules may enhance pharmacy students’ understanding of substance dependence issues and attitudes.

One college of pharmacy in the United States, in addition to a required substance abuse course, offers an elective to illustrate addiction recovery principles. Students taking the elective are asked to give up a habit that is causing them problems for six weeks and they meet weekly to discuss the addiction recovery process. This course has been offered for 15 years and 50 per cent of the substance abuse course students are enrolled (Baldwin, 2008).

From the client consultation interviews

Clients’ need for pharmaceutical care

“I would have liked to know more about methadone before I started. It would have helped me make a better decision. You shouldn’t just tell a sick person ‘this will make you better.’ ” “There has been a lack of care and communication and confusion with my HIV meds. The methadone wasn’t holding me due to medication interactions.” “I felt sick for weeks and didn’t know it was because my dose was too high.”

The panel recommends that:

17. Professional organizations, addiction and mental health agencies and pharmacists’ employers promote the development of, and provide encouragement for all practising pharmacists to participate in, educational events on substance abuse and opioid dependence, including the growing problem of prescription opioid abuse. [III]

Most pharmacists receive little training on opioid dependence and treatment in their undergraduate experience, and it is important that all pharmacists further their knowledge in this area, even if they are not yet providing MMT services. There are indications that abuse and dependence on prescription opioids is increasing in Ontario and Canada. There was an increased number of patients addicted to prescription opioids entering the CAMH methadone maintenance program following the rapid expansion in the availability of MMT in Ontario in the 1990s (Brands et al., 2002; Brands et al., 2000). More recently, the number of individuals seeking detoxification treatment from controlled-release oxycodone at CAMH has also increased significantly (Sproule et al., 2009). In addition, in a cohort study of illicit opioid users, the proportion using prescription opioids increased from the year 2002 to 2005, with regional differences noted across Canada (Fischer et al., 2006). Pharmacists need to increase their knowledge base in prescription opioid addiction, particularly to understand the difference between addiction and physical dependence. Continuing education programs on pain treatment rarely (or inadequately) discuss the issue of opioid abuse and dependence.

A survey in British Columbia of 257 pharmacists (Cohen & McCormick, 2008) found that a slight majority reported training on how to identify signs of prescription drug misuse or abuse. This training was more common in younger pharmacists. The mean amount of training was 13.6 hours. Many pharmacists learned to identify prescription drug misuse through personal experience: they detected multi-doctoring using the provincial PharmaNet prescription drug profile or by recognizing early refills of prescriptions. Most intervened by calling the physician to confirm prescriptions or by confronting the customer directly. The primary reason they gave for not intervening was concern over how the customer might react (i.e., they were afraid that the client would be confrontational or they feared for their own safety). Pharmacists recommended additional training on prescription drug misuse.

Jones et al. (2005) surveyed 42 community pharmacists in Wales and found that at one month after a structured educational evening event there was little maintained change in attitudes. This suggests that changing attitudes is a long-term process. There is a need for reinforcing changes through continuing education.

Practising pharmacists (484) in Florida were surveyed while attending continuing education programs (Lafferty et al., 2006). Of the respondents, 67.5 per cent reported participating in two or fewer hours of addiction/ substance abuse education in pharmacy school and 29.2 per cent said they had received no addiction education. Pharmacists who had more education counselled clients more frequently and felt more confident in dealing with substance abuse clients. Of those surveyed, 53 per cent reported they had never referred a patient to substance abuse treatment in their whole career.

Brooks et al. (2001) conducted a survey in the United States of 556 pharmacists, comparing those who had taken training in addiction treatment to those who had not, and found that those who had taken training would more likely refer clients to community resources and be more involved in working with their chemically dependent clients.

The panel recommends that:

18. The Ontario College of Pharmacists revise the current requirements for pharmacies providing MMT services to mandate earlier training to promote safety. The designated manager and one pharmacist must complete the training within six months of starting to dispense methadone. [IV]

19. CAMH or another approved provider of methadone training develop a brief electronic document (e.g., one page) outlining the key safety features of providing MMT services that can be made available for immediate use by pharmacies initiating MMT services. [IV]

20. CAMH produce an electronic version of its most recent pharmacist’s guide to methadone maintenance treatment that can be purchased online and downloaded immediately so that pharmacies initiating MMT services can access it without delay. [IV]

21. CAMH make the online component of its Opioid Dependence Treatment Course available immediately upon enrolment to pharmacists new to providing MMT services, with the stipulation that these pharmacists attend the workshop component within six months of beginning the course. [IV]

22. CAMH or another approved provider of methadone training monitor and respond to waiting lists for training programs by, for example, offering the training more frequently or by exploring other delivery methods, such as webinars or video conferencing, to help meet the needs of pharmacists in remote areas. [IV]

Since undergraduate training on substance abuse and opioid dependence is lacking, most pharmacists do not have an adequate knowledge base from which to provide MMT services safely.

Having the most essential knowledge and references easily accessible and as early as possible will help facilitate pharmacies starting a methadone service and assist those who are deciding whether to provide MMT.

The online component of the CAMH Opiate Dependence Treatment Interprofessional Education Program would provide a good introduction to providing service, and a brief methadone information sheet would complement this program. The methadone information sheet could include some of the key points in providing MMT service, for example, observing dosing, diluting dose in orange drink, identifying the client, assessing the client for intoxication and informing the prescriber of missed doses.

Having a current version of the CAMH Pharmacist’s Guide available in a downloadable format would enable pharmacists to have this mandatory reference as soon as they need it. The other two references pharmacists dispensing methadone require, the CPSO Methadone Maintenance Guidelines and the OCP Policy for Dispensing Methadone, are currently available electronically.

The panel recommends that:

23. The Ontario College of Pharmacists and providers of methadone training collaborate on ongoing training requirements based on needs identified during the College’s pharmacy inspection process. [IV]

The Ontario College of Pharmacists undertakes regular inspections of community pharmacy practice in the province. Practice issues related to methadone service provision identified during these inspections could be shared with educational service providers for consideration in future training initiatives. This would be an effective mechanism for updating methadone training to reflect current practice issues in the field.

The panel recommends that:

24. CAMH or another approved provider of methadone education deliver methadone training in a manner consistent with interprofessional education principles. [IV]

Since MMT practice is best delivered in a collaborative manner (Health Canada, 2002), a multidisciplinary approach in education will prepare pharmacists to work effectively with other health professionals as a team.

The panel recommends that:

25. The Ontario College of Pharmacists and community colleges providing pharmacy technician training develop core competency requirements for regulated pharmacy technicians providing MMT services. [IV]

Pharmacy technicians are important members of the pharmacy team. They may be involved with preparing and dispensing methadone, and interact with MMT clients in the pharmacy. Core competencies should be developed and educational programs designed to optimize the role of pharmacy technicians in the safe delivery of methadone services. This issue may be particularly important in view of the new regulated status for pharmacy technicians that will be implemented soon in Ontario, where pharmacy technicians will be able to take more responsibility for dispensing.

The panel recommends that:

26. CAMH or another approved provider of methadone education undertake a needs assessment of pharmacists who have participated in the initial MMT training, and then use this information to develop an updated or advanced MMT course for pharmacists. [IV]

27. Professional pharmacy organizations, the Ontario College of Pharmacists, pharmacy managers/owners and hospital pharmacy directors encourage pharmacists to take courses on motivational interviewing, intervention strategies to use with difficult patients, and concurrent disorders, to enhance pharmacists’ skills in dealing with opioid-dependent clients. [IV]

Pharmacists who are already in MMT practice and have taken initial MMT training may wish to update and improve their skills. Since pharmacist training is recommended by the Ontario College of Pharmacists every five years, a new, higher level course would meet the needs of this experienced group of providers. Pharmacists who have taken initial MMT training should be surveyed for their input about topics to include within this higher level course. This advanced training could include, for example, methadone use in pregnancy, in patients with concurrent disorders (e.g., pain, psychiatric disorders, HIV) and in other special populations.

Any interaction with a client has therapeutic potential. Pharmacists using motivational techniques in their interactions with clients may enhance clients’ treatment. The issue of dealing with difficult, demanding clients has been identified by pharmacists as an area in which they would like more training (Cohen & McCormick, 2008). Training in de-escalation techniques to avoid potentially unsafe interactions could help pharmacists achieve greater satisfaction in their practice, as well as improve client outcomes.

The panel recommends that:

28. Drug information service providers ensure that staff is trained on and familiar with common issues in MMT treatment and have a mechanism to refer to experts when necessary. [IV]

Pharmacies must subscribe to a drug information provider service. The staff at the drug information provider should be able to respond to general questions on MMT and substance abuse. To do this they would require training in MMT to understand the patient safety issues and relevant guidelines. For more complex questions, the drug information service should have an arrangement with expert service providers to assist in consultation.

The panel recommends that:

29. Professional pharmacy organizations develop a mechanism in conjunction with the Ontario College of Pharmacists to ensure that pharmacists dispensing methadone are informed in a timely fashion of new educational resources available. [IV]

A timely direct communication via e-mail from the Ontario College of Pharmacists, the Ontario Pharmacists’ Association or another professional pharmacy organization is recommended when any new methadone-related item is posted on the website of either the OCP or the CPSO.

The panel recommends that:

30. Professional pharmacy organizations, CAMH and funding agencies develop a mentorship program to link new methadone service providers with experienced providers. [IV]

31. Professional pharmacy organizations and CAMH promote the CAMH Addiction Clinical Consultation Service to pharmacists providing MMT services. [IV]

The Addiction Clinical Consultation Service (ACCS) is a service provided by CAMH. It is designed to serve health and social service professionals, including pharmacists, who have client-specific questions related to substance abuse. The accs is not designed to deal with health emergencies or immediate or legal issues. The health care worker calls a central phone number and, depending on the question, accs may provide referral to a consultant team member (physician, therapist/counsellor or pharmacist) who will communicate with the health care worker within four hours. Awareness of the service should be promoted to support pharmacists providing methadone services.

Hepatitis C Treatment of Substance Users in Pharmacotherapy for Addiction

Introduction:

Hepatitis C, Substance Use,
and Dependence
Illicit drug and alcohol abuse and dependence are problems
of major medical importance in the United States, leading
to high rates of morbidity and mortality from end-stage
liver disease. The prevalence of illicit drug use in the United
States, as estimated by the National Survey on Drug Use
and Health in 2002, stands at 19.5 million Americans above
the age of 12; half of Americans aged 12 or older (51.0%)
reported being current drinkers of alcohol, an estimated
120 million people [1•].

Salient illicit drug use and practices
are presented in Table 1. The Centers for Disease Control
has estimated that 60% of all new cases of hepatitis C are
related to injection drug use [2]. Injection drug practices
include the use of heroin, cocaine, methamphetamine, and
prescription opioids (Table 1).

It has been estimated that
there are at least 800,000 untreated injection-heroin users
[3]. However, the population of opioid-drug users may be
grossly undercounted, because some surveys have found up
to three times more illicit drug users in particular regions
than commonly estimated [4].
Drug addiction is a chronic, relapsing neurophysiologic
disease resulting from the prolonged neurologic
effects of drugs. The neurochemical abnormalities resulting
from chronic use, such as opioids, underlie many of the
observed physical and behavioral aspects of addiction
(Table 1). The brain abnormalities associated with addiction
are wide ranging, complex, and long lasting [5,6].

They can involve genetically abnormal brain signaling
pathways, social factors, psychological conditioning or
stress, and result in cravings leading to a predisposition to
relapse even months or years after drug use cessation.
Recent studies have identified risk factors for the transition
to injection drug use that include the following: emerging
drug practices, differential characteristics of opiate injectors
versus inhalers, and patient-related factors that predict
entry into substance abuse treatment [7•,8].

The importance
of limiting individuals from progressing to injection
drug use can be vividly seen from data comparing the
hepatitis C incidence between injection and noninjection
drug users [9]. This longitudinal surveillance study in
New York City showed an annual incidence rate of
hepatitis C in young noninjection drug users of 0.4 per 100
person-years compared with 35.9 per 100 person-years in
injection drug users (IDUs).

Thus, delaying or preventing
the transition to injection drug use can have a significant
health benefit by reducing the risk of comorbid conditions
associated with substance abuse and addiction.

read the full file here: 002_HP04-3-1-05

How Methadone Clinics Work!

Methadone maintenance is somewhat of a mystery to clinicians not involved in addiction medicine, and opioid addicts don’t fare well in the emergency medical system. Many nurses and physicians have trouble dealing with them objectively and don’t want to be involved. Well-managed methadone maintenance is, however, a different story. Few EPs dole out methadone, but maintenance patients show up in the ED with legitimate complaints. Patients on high-dose methadone can experience painful conditions or injuries requiring additional analgesia. It’s not easy, but if one can put aside preconceived notions about addiction, methadone maintenance presents a fascinating challenge to the EP.

Figure. Clients line…

Most  have treated methadone maintenance therapy (MMT) clients in the ED, and have dealt with withdrawal, missed appointments, and overdose. I have visited a few methadone clinics, and the whole concept is fascinating, giving great insight into a government-sponsored medical entity.

Treatment Improvement Protocol Series 43: Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Program

This massive document summarizes the consensus of the U.S. Health and Human Services on MMT, which is administered through the Substance Abuse and Mental Health Services Administration and the Center for Substance Abuse Treatment, branches of HHS. This 14-chapter document has everything you want to know about MMT.

Edit by Exilope: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hssamhsatip&part=A82676

Initial Screening: Anyone can walk into an MMT clinic and request treatment. Initial screening exams and interviews determine the applicant’s eligibility and the process includes an assessment of their readiness to accept treatment. Ongoing, if not daily interventions, are required to keep the patient in the system and off the opioid. The addiction severity index collects basic information, and it can be used to track progress. Much of the information is supplied by the addict, and truthfulness on their part is paramount for success.

Comment: I suspect most people don’t walk in off the street thinking about MMT for the first time. All potential clients likely consider it many times or talk about it with fellow addicts. They are often prompted to try MMT by those who have been through the process, some more than one time. One would assume that an opioid addict who shows up at the clinic has hit rock bottom or finally has accepted they have an addiction they cannot control. Many are in overt withdrawal. They are ready to sign up.

First impressions are lasting ones. The HHS recommends a plethora of warm and fuzzy approaches to help the addict adjust and feel supported. A nonconfrontational and nonaccusatory attitude is stressed. Unlike the ED, MMT clinics want to be in the business of dispensing methadone. Clinics are usually prepared to provide immediate information, if not methadone treatment, on the first day.

A variety of preprinted documents are handed out that describe the services, rules, and expectations of the program. Policies are in place to deal with disruptive and violent clients and pregnant women. Clinics also try to identify treatment barriers and offer financial assistance and psychiatric crisis intervention. Many patients also have underlying psychiatric disorders, legal difficulties, child care issues, and transportation and family concerns. Cultural, ethical, and spiritual factors also complicate MMT. Those patients who seem in crisis can be referred for inpatient medical facility or psychiatric care. The correlation between opioid addiction and the risk of suicide is well known, and initial screening and periodic assessment helps determine that ongoing risk.

Admission Issues: A significant delay between the first contact, initial screening, and methadone treatment, especially failure to quickly address withdrawal, adversely affects the number of applicants who enter the program. It’s difficult to deal with an opioid addict in withdrawal; his patience wears thin, and he wants treatment now. Recognizing the realities of crowding and limited resources, MMT clinics can provide an interim maintenance program without formal screening or actual admission to the site. By federal regulation, medication can be administered for up to 120 days with only minimal screening procedures.

Violent or threatening patients can be turned down, but I have been amazed at how understanding and supportive some of the staff are; it’s similar to the mentality emergency physicians use to treat those who are not the nicest people. MMT, like emergency medicine, is a service industry, and the customers often possess the mentality of the McDonald’s client. They want it now, they want it their way, and they don’t want to pay much for it. Frustrated clients who elope are, however, a loss for everyone. Programs are not free, and cash and insurance are accepted, but often the down-and-out addict qualifies for local aid.

Information, Collection, and Dissemination: During the first few visits, a substance abuse history is obtained, and treatment options are discussed. Consent to treat is elicited, and addicts must sign a bevy of documents that provide further information on the multifaceted MMT process. Patients must be 18 or have parental approval. Otherwise, the services are confidential even to family members. Confidential information is not given to any inquiry except the court. The specifics of the individual’s opioid addiction, including recent pattern changes and binges, are gathered. Other drugs such as benzodiazepines and alcohol are often confounding issues, and the patient’s daily pattern of opioid abuse is determined, essentially by his own admission.

The opioid withdrawal history and the energy required to maintain the addiction is sought. Many patients are in withdrawal when they come to the clinic, making historical information open to exaggeration, but many downplay their use (like the alcohol history obtained in the ED). Some withhold a history of other addictions, perhaps thinking they might supplement the methadone if needed. Blood tests for specific drugs are not required nor usually performed to quantify use. A serum drug level is of no value in this scenario. Questioning the history can intimidate the prospective client and set up an adversarial relationship at the beginning. Again, unlike the ED, MMT clinics put a lot of trust in the truthfulness of the addict.

Medical Assessment: The aim of medical assessment is to determine the safety of methadone use. The drug is often dispensed on the first visit because of withdrawal. It is generally required that someone be addicted for one year before admission. There appears to be some flexibility in this criterium, especially for prisoners, pregnant women, or those previously treated. There may be uncertainty about past narcotic use, but generally a broad definition is accepted for opioid addiction, and one need not administer Narcan to test for withdrawal.

Generally, the staff obtains a medical history that documents drug-related diseases such as hepatitis, AIDS, tuberculosis, or STDs. Within 14 days of admission, a basic physical examination is performed, including blood tests for HIV, syphilis, and hepatitis. Federal regulations do not require a full panel of laboratory tests; that appears to be a state issue. Patients usually are tested randomly by a urine screen immunoassay test for additional drug abuse at least eight times each year per SAMHSA. Because methadone does not yield a positive opioid result unless specifically tested, a positive opioid screen usually means exogenous drugs.

Multiple Substance Abuse: It is common knowledge that opioid addicts often abuse other substances, especially alcohol, amphetamines, benzodiazepines, prescription opioids, cocaine, sedatives, and marijuana. CNS depressants are particularly dangerous when combined with opioids. Patients generally are asked to report other substances they used in the past. The accuracy of this form depends, of course, on patient honesty. Alcohol is a favorite of most, and heroin addicts particularly like to add cocaine for additional euphoria. Benzodiazepines are commonly used to boost methadone and enhance the high. Patients also self-medicate because of withdrawal symptoms or because they are anxious, depressed, or lonely.

MMT clients all know using an exogenous substance can kill them and defeat the purpose of MMT. Using exogenous drugs negatively affects attendance rates and cooperation with other programs. Interestingly, patients are not frequently discharged from MMT because they abuse other substances. The main goal is to retain the patient in MMT, allowing for human frailty, lack of self-control, and poor judgment. MMT clients are given multiple chances despite violating explicit rules and regulations.

Drug Testing: Clients are randomly tested for other drugs, usually with an immunoassay urine screen. This is not a perfect system because it only identifies those using other substances frequently and only detects drugs that show up on a urine screen. Of course, it has to be your urine, and there is always someone around who wants to give a clean sample for the right price.

Periodic drug testing provides objective evidence of treatment success and monitors patient progress. Typical urine testing evaluates for commonly abused substances with a qualitative immunoassay technique that has cutoff concentrations. Testing drug levels in the blood is not helpful because tolerance, time of use, and the need to send the test to a reference lab does not allow for meaningful interpretation of data. Most drugs remain in the system and are excreted in the urine for two to four days following use. Measuring methadone serum levels during treatment has minimal value and is not done routinely, but this may be used to identify a rapid or slow metabolizer. Obviously, urine tests are not quantitative; they merely give positive or negative results.

Urine collection may be monitored to avoid contamination or substitution. There are no firm and fast rules for the method of testing, and direct observation is not mandatory. The most common test is an enzyme-multiplied immunoassay technique (EMIT), which uses antibodies to specific drugs or metabolites. Oxycodone is often not identified with this test; nor are clonazepam, Seroquel, hallucinogens, fentanyl, Demerol, dextromethorphan, propoxyphene, and a variety of street drugs. On-site dipstick urine testing is common, but some clinics will confirm the initial clinic screen via a reference laboratory. Many clinics test patients at intake to prove they used opioids recently. The continued use of heroin or other opioids may prompt an increase in the methadone dose because it’s common to supplement during withdrawal.

Retaining Patients in MMT: The longer the patient stays in MMT, the less likely he will revert to using opioids. Staying in MMT for more than a year is associated with constructive lifestyles changes, decreased criminal behavior, and less transmission of infectious diseases. Older patients and those not in the criminal justice system tend to stay in the program longer. Those who have tried it before and failed are better candidates for retention the next time around.

But the key to MMT success, as this HHS publication notes, is: Adequate individualized medication dosages are probably the most important factor in patient retention because they contribute to patient comfort and satisfaction by reducing withdrawal symptoms and craving. The serum half-life of methadone is stated to be 24 to 36 hours, but in reality there is an extremely wide range (13-58 hours). Excessive methadone use occurs when daily visits and individual dose adjustment are not made.

Take-Home Medication: Methadone is usually dispensed daily in a liquid form, and ingestion is witnessed. This keeps patients from diverting tablets. Methadone diversion is a huge problem in this country, but that methadone is usually not obtained from clinics. A single take-home dose is common on Sundays and holidays. After six months to a year, compliant and reliable patients can take home one to four weeks of methadone, but initially, doses are only dispensed daily at the clinic. The requirement to show up every day can be problematic.

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Dosing Schedule: A dose of 30 mg to 40 mg of methadone is the upper limit for the initial dose, per regulation. Initial dosing should be followed by increases over subsequent days until withdrawal symptoms are suppressed. A steady state of a dose is not reached for three to five, sometime seven days after a dosage change. The goal is to reach 80 mg to 120 mg methadone per day, a level that has been proven to improve compliance to the program. Using smaller doses or failing to increase the dose when withdrawal is still present is ineffectual and counterproductive. Withdrawal often prompts exogenous drug use or elopement.

The actual schedule is not set in stone, but daily dose increases of 5 mg to 10 mg a day for the first five to seven days to reach 60 mg a day are common. The 60 mg per day dose is maintained under daily observation to reach a steady state. The first week or two of MMT are the most dangerous for the patient and the time during which most fatalities occur. With daily observation and individual dose adjustments, induction is safe and effective as long as the patient is truthful and abstains from other drugs.

The quoted serum half-life of methadone can be misleading, and provides only a rough estimate to forecast dosing requirements and effectiveness. Methadone is eliminated more quickly from the blood and the effects wear off sooner until sufficient levels are obtained to saturate tissues, especially the liver. Smokers have increased clearance, and significant liver damage slows clearance. The optimal dose can only be determined by observing the individual daily, debriefing him on how he feels, and altering dosages in a safe, effective manner.

There is no uniformly suitable dose range or limit for all patients. Some require 400 mg to 700 mg a day while others do well on 80 mg to 120 mg a day. During induction, clinical observation and patient symptoms are the best indicators of whether a dose is too small or large. When this protocol is followed, methadone induction is safe and effective.

Comment: There are eight MMT clinics in Philadelphia, usually for heroin addiction, but more frequently for prescription opioid addiction. Most opioid addicts know the concepts of MMT well, and visit various clinics off and on throughout their addiction. The rules of MMT are straightforward, and each state is allowed some latitude on various issues. Some addicts have learned to work or abuse the system, but MMT is a godsend, if not a true lifeline, for many opioid addicts.

Addiction to hydrocodone, hydromorphone, and oxycodone is likely more widespread than street heroin. There is little difference between the prescription pill addict and the hardcore street heroin user on everyday issues or potential benefit from MMT. The well-to-do business man, the bored housewife, the professional athlete, or the Hollywood celebrity seem to prefer pills over the needle. Some physicians readily prescribe a slew of addicting medications, prescriptions are stolen or altered, and anyone can buy a few Percocet at the local high school. The Internet provides drugs as well as directions on use and how to beat drug tests and avoid overdose. Of course, heroin can be smoked and snorted as well, but there is less of a stigma involved with popping a pill than buying a bag of heroin on a lonely street corner.

I am quite impressed with the understanding approach to MMT and the dedication of the clinic personnel. Methadone manufacturers stress that their product should be used only under strict HHS guidelines, and they actually reference the Federal Register code in the package insert. The dangers of inappropriate methadone use are well-reported in the literature, but it’s likely an underused drug for chronic pain control.

Society has written off many opioid addicts or would drop them in a heartbeat at any sign of deceit or additional drug use. Not so for MMT clinics; they bend over backwards to give everyone yet another chance. Using additional substances during MMT is very common. Klonopin, Xanax, Soma, and Seroquel are popular in my area to boost methadone’s high, and none show on a urine screen. It’s easy to buy any of these on the street, usually right outside the door of the clinic. It’s best to never underestimate the ingenuity or resourcefulness of an opioid addict so MMT works best in an environment of mutual trust and truthfulness. Lying to the counselor about past or present drug use or beating the drug test is tempting, but in the end, it can be a fatal error.

Interactions!

Buprenorphine interactions

Although there is significant confusion in the literature, buprenorphine is most commonly classified as a (partial) mu agonist/kappa antagonist. There is consensus that in the relatively ‘low doses’ used in clinical pain management, (5-100 mcg per hour), buprenorphine behaves like a ‚full‘ mu agonist. The partial agonist/antagonist effects seem only to become relevant for analgesia in very high doses used to treat opioid addiction (8-32 mg per day).

In patients on ‘analgesic doses’ of buprenorphine (eg transdermal), one can continue to use opioid analgesics for breakthrough pain in the usual way with good effect. The partial agonist/antagonist effect on supplemental opioid analgesia is not a major clinical issue. Other alternatives include sublingual buprenorphine or tramadol.

When treating acute pain after major surgery or trauma in patients on ‘high dose’ sublingual buprenorphine for addiction, continue the buprenorphine, using maximal multimodal analgesia including ketamine and neural blockade, supplemented with opioid PCA (using higher bolus doses) and monitoring the patient closely for adverse effects. In our experience, many patients undergoing major emergency surgery seem to do well with continuation of high dose sublingual buprenorphine and PCA fentanyl or morphine in appropriate doses. Conversion to standard opioids is complicated and often unnescessary.

Methadone interactions

Because methadone ‘saturates’ CYP450 (3A4) at low plasma levels (low hepatic clearance) compared with other opioids, it’s very ’susceptible‘ to;

• The effects of a 30-fold variation in CYP450 enzyme activity between patients (fast, medium or slow methadone metabolisers), thus explaining the wide range of t1/2 (5-150 hours) and in part, highly variable clinical responses to methadone loading.
• ‘Plasma accumulation‘, as the dose or frequency increases (the ’saturated‘ CYP450 can’t ‚burn off‘ the excess methadone):
• Complex interactions with many drugs that share CYP450 for metabolism, particularly anticonvulsants, antidepressants, anti-microbial and antiretrovirals.

When prescribing methadone, always think about drug interactions at CYP450. Interactions are complex, with either induction (eg. phenytoin, rifamycins) or suppression (eg. fluvoxamine, fluoroquinalones, macrolides) of enzyme activity affecting methadone clearance, sometimes resulting in either withdrawal or accumulation respectively.

Methadone is highly-bound to plasma acute phase reactants (a1-acid glycoprotein), with the free methadone concentration decreasing when the level of phase reactants is raised (the free methadone is ‘mopped up’) such as in cancer or sepsis, leading to reduced analgesia or in rare cases withdrawal.

There are also substantial risks of over-sedation when methadone is combined with benzodiazepines, alcohol or THC.

Methadone, prolongs the QT interval in a dose dependent fashion (usually in doses greater than 200 mg per day) with case reports of Torsades de Pointes and VT. Check an ECG before commencing methadone, keep doses low and consider potential interaction with other drugs and conditions that prolong the QT interval.