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.

Ouch! Abrupt opioid withdrawal increases pain sensitivity!

(PhysOrg.com) — The abrupt withdrawal of morphine-like analgesics – opioids – can increase sensitivity to pain. Experiments have now shown that this effect is caused by a memory-like process, the long-term potentiation of synaptic strength in the spinal cord. The study, which was supported by the Austrian Science Fund (FWF), also found ways of avoiding this increase in pain sensitivity. These pioneering results have now been published in the prestigious journal Science.

Opioids are the oldest and most effective analgesics. They are often used, for example, during operations or when other forms of treatment fail. This is because opioids – unlike other analgesics – bind to opioid receptors, which are highly effective in depressing the activity of nerve cells responsible for transmitting information about pain. On abrupt withdrawal, e.g. after surgery, this can lead to an abnormal, excessive increase in pain sensitivity. A research project conducted by the Department of Neurophysiology at the Center for Brain Research at the Medical University of Vienna has now been able to explain what causes this phenomenon.

Painful „cold withdrawal“

The abrupt withdrawal („cold withdrawal“) of opioids leads to „long-term potentiation“ (LTP) of synaptic strength in the spinal cord’s pain pathways. This in turn leads to sustained and increased sensitivity to pain. In the brain, LTP is a physiological mechanism for learning and memory. An activity-dependent increase in synaptic transmission between the nerve cells at their contact points, the synapses, can be very long-lasting. For example in the spinal cord, pain stimuli can trigger LTP and lead to a long-lasting „pain memory“. This study proves for the first time that opioids also leave a „memory trace“ in the pain system if they are withdrawn abruptly. „We were rather taken aback ourselves by the results,“ said project manager Professor Jürgen Sandkühler. „Until now, we had assumed that only strong or sustained pain could induce LTP in the pain system.“ On making this discovery, Prof. Sandkühler and his team set about deciphering the molecular mechanisms of this process. Dr. Ruth Drdla and Matthias Gassner, the two main authors of the study, were able to show that abrupt withdrawal – similar to a pain stimulus – increases the concentration of calcium ions in the spinal cord’s nerve cells.

Excessive calcium ions

Calcium ions are important intracellular messengers that activate numerous enzymes and consequently also lead to LTP. With memory LTP, calcium ions flow into the brain’s nerve cells via NMDA receptor channels. Therefore, the research team conjectured that blocking these calcium channels could also prevent LTP in the spinal cord. „To test our theory, we used selective blockers that only close off NMDA receptor-type calcium channels,“ explains Prof. Sandkühler. The results showed that these blockers, which are also available as drugs, did indeed reliably prevent LTP on the withdrawal of opioids. „However, the blocker has to be administered in good time before the start of the withdrawal,“ adds Prof. Sandkühler. The team also made another discovery that is important for the treatment of pain: If the opioid is reduced slowly and in a controlled
manner instead of being withdrawn abruptly, it is quite straightforward to prevent the LTP caused by opioid withdrawal and, therefore, the onset of withdrawal symptoms.

This latter result of the FWF-supported project in particular shows that fundamental medical research can indeed provide concrete recommendations for everyday medicine. These new findings mean that essential opioids can be applied even more reliably in the treatment of pain – without any nasty surprises once they are withdrawn.

More information: Ruth Drdla, Matthias Gassner, Ewald Gingl and Jürgen Sandkühler. Induction of synaptic long-term potentiation after opioid withdrawal, Science 325 (2009), July 10th. DOI: 10.1126/Science/1171759.

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Enhancing Recovery with Meditation and Mindfulness

There are several promising applications of mindfulness to enhance recovery from alcohol and drug dependence and other addictions. This article explores several new trends and ways that meditation and mindfulness can be used to complement and help with recovery.

The Buddhist teachings (dharma) focus on the healing power of compassion. To recover from an adversity (i.e., addiction) gives one an opportunity to be more compassionate toward others as well as toward oneself.

Using mindfulness in counseling

Mindfulness has gained wide acceptance from counselors in the mental health and addiction recovery fields. Over the last 15 years the psychology field has seen a resurgence of mindfulness being used for the treatment of stress, anxiety, depression and personality disorders. For instance, John Kabat-Zinn used mindfulness training and meditation to help clients with stress, pain and anxiety disorders Kabat-Zinn (1992); Marsha Linehan (1993) integrated mindfulness practices in her Dialectical Behavior Therapy (DBT) for the treatment of personality disorders; Steven Hayes (1999) developed Acceptance and Commitment Therapy (ACT) for the treatment of depression and anxiety; Zindel Siegal et. al. (2002) developed Mindfulness-Based Cognitive Therapy (MBCT) as a relapse prevention approach to depression.
Thus, it makes perfect sense that Buddhist teachings (dharma), meditation and mindfulness training would be an ideal tool to help in the treatment of addictions.

Buddhism and addiction

Buddhist teachings make several references to addictions. Addictions often prevent individuals from being present and aware, conscious of what is going on with others and themselves. People often fail to realize what is really important. They often forget that they are not in control, and are prone to self-deception.

“Buddhist literature offers considerable insight into the basic nature of addiction, how addictive behavior develops, and how meditation can be used as a method of transcending a wide variety of addiction problems,” said Dr. Alan Marlatt, director of the University of Washington Addictive Behavior Research Center and an expert on alcohol/drug relapse prevention (Marlatt, 2002).

Buddhism describes addiction as being “a false refuge” — a delusional place to try to hide and escape from being present in life. Buddhism also describes addiction in the context of grasping, resisting and delusions; the mindfulness counters are listed below.

The grasping is the craving, obsession and compulsion to use alcohol/drugs, and the accompanying addiction-related behaviors. Grasping is described in the three “Cs” in our functional definition of addiction — compulsion and obsession, inability to control and continued use despite negative consequences.

The resisting is the pushing away, the isolation, the shutting down of normal human pleasure and displeasures, the withdrawal from connection with others — the invoking of the “no talk, no feel, no trust” rule, and of course, “not asking for help.” The Alcoholics Anonymous proverb “Silence is the enemy of recovery,” describes this resistance. Resistance is demonstrated by denial, delusion and rejecting advice, help and direction from others.

Addiction — “Land of the Hungry Ghosts”

Dr. Thomas Bien and Dr. Beverly Bien, authors of Mindful Recovery (2002), and Finding the Center Within (2003), describe a strange and peculiar realm in Buddhist cosmology, called the “land of hungry ghosts.” People in this land are described as having huge appetites, but unable to satisfy them.

Addiction is viewed in Buddhist teachings as the inability to see the abundance in our lives, nor the joy that is there “in the now.” Bien and Bien describe the torture of addicts as “…. not lack, but the inability to open to the surrounding abundance …”

“We do not need to fill ourselves with new things — we need to experience more fully what is already there,” the authors state in their book, Finding the Center Within (Bien & Bien, 2003).

Meditation and Alcohol/Drug Recovery

Bien and Bien, in their book Mindful Recovery, describe meditation and mindfulness as helping the person develop a “quality of calm awareness.” The authors further describe this as a perfect antidote to the “addicted state of mind.”
In a study conducted by the authors, three groups of heavy alcohol users were given different treatments: one group received deep muscle massage sessions for six weeks; another group did silent reading for six weeks; and the final group had six weeks of meditation sessions. The meditation group decreased their alcohol consumption by 50 percent (the highest of all groups). The meditation group also chose to continue their meditations for longer than the other groups continued their respective practices.

Meditation, twice a day for 20 minutes per session, allows the recovering person to let thoughts and feelings (positive and negative, pleasurable and unpleasurable) to stream through consciousness without attaching to them, holding them at arms’ length, observing and reflecting, rather than reacting.

Delusion and Denial

Recovery from alcohol and drug addiction involves breaking through “denial” and admitting you are powerless over these substances. The old joke in the alcohol/drug recovery field was that denial is a river in Egypt (de-Nile). A more contemporary description of d-e-n-i-a-l stands for: I don’t even know I am lying.

Buddhism has a similar focus on denial, and frequently talks about “delusion” and how we deceive ourselves from accepting suffering as part of our lives. In Buddhism, the goal is to be more aware and present by overcoming our deceptions in our life.

Pema Chodron says it well: “The essence of bravery is being without self-deception” (Chodron, 2001).
The 12 Steps and the Eightfold Path

Mindfulness is very compatible with Alcoholics Anonymous (AA) and Narcotics Anonymous (NA), and the 12-step principles. Kevin Griffin, author of One Breath at a Time, describes the many similarities and differences between the 12 steps and the Buddhist Eightfold path. One of the similar teachings of these two is Rigorous honesty and Right Speech.

A major problem in addiction is the addict’s deception, dishonesty and outright lying. The Big Book and AA emphasize rigorous honesty to counter the rationalized lies and deceptions that are often a part of the disease. In a similar way, the third path of the Buddhist Eightfold path talks about Right Speech, which is speech that is truthful, helpful, kind and appropriate. Lies are expanded to include exaggerations, half-truths, omissions, denials, rumors and gossiping. Right Speech goes even further in describing right speech as not harming others, being kind, melodious, aesthethic and compassionate, accepting and understanding of others.

There also are many common teachings, expressions and proverbs that are paralleled in the teachings of AA and Buddhist dharma, including:

The Eightfold Path includes the following: Right View; Right Intention; Right Speech; Right Action; Right Livelihood; Right Effort; Right Mindfulness; and Right Concentration. The term “right” is used not in the context of right or wrong, but instead as the preferred way or suggested way.  “Right” also means wholeheartedness and goodness.

Compassion for self and others

Life is difficult enough without beating yourself up. Give yourself a break, lighten up, and “stay in the now.”
“All beings want to be happy, yet so very few know how. It is out of ignorance that any of us cause suffering for ourselves or for others,” said Sharon Salzberg, in her book, Loving Kindness.  Buddhism teaches compassion for oneself and for others. Shame, self-blame, criticism, judgments, anger and isolation cause and contribute to problems with alcohol and drugs. They can be countered by developing compassion for oneself and for others. Buddhism is a different way of viewing oneself and others. It is the way of compassion, reflection and goodness. Compassion also involves forgiveness. Forgiveness can allow a person to open his or her heart and live with greater compassion and love.

In his book, The Wise Heart, Jack Kornfield said, “For most people, the work of forgiveness is a process. Practicing forgiveness, we may go through stages of grief, rage, sorrow, hurt, and confusion. As you let yourself feel the pain we still hold, forgiveness comes as a relief, a release for our heart in the end. Forgiveness acknowledges that no matter how much we may have suffered, we will not put another human being out of our heart.”

In my book, Awakening to Mindfulness, I’ve outlined 10 Steps of compassion:

1. Being sensitive to others’ suffering, as well as your own suffering
2. Being reflective (gentle) instead of reactive
3. Changing critical attitudes (greed, hatred, delusion) into caring attitudes (generosity, love and awareness)
4. Being truthful, helpful, kind and appropriate
5. Not blaming, taking responsibility
6. Not complaining or dramatizing
7. Invoking “right speech” and following the eightfold path
8. “Cherishing” others
9. Avoiding and reducing criticism, contempt, defensiveness and stonewalling in relationships
10. Having the grace to love and to be loved

Mindfulness-based behavioral relapse prevention (MBRP)

Dr. Alan Marlatt and his associates at the University of Washington have been exploring the application of mindfulness and meditation in preventing relapse to alcohol/drugs. He has found that “the heightened state of present-focused awareness that is encouraged by meditation may directly counteract the conditioned automatic response to use alcohol in response to cravings and urges” (Marlatt, 2007).

MBRP helps the recovering alcoholic/addict to recognize (not suppress) the negative emotional states, keeping them at arms’ length. Ironically, trying to suppress negative thoughts results in an increase, rather than a decrease, in negative thoughts (Bowen, 2007). The negative thoughts are identified as “normal thoughts” at various stages of recovery. These negative thoughts are accepted as thoughts that the individual does not have to choose to act on.

An example of a MBRP technique is “urge surfing,” which involves visualizing your “urge” to use (alcohol/drugs) as having a cycle much like a wave. The wave has a crest, it crashes and then rolls to shore and disappears. This technique involves using your breath as a surf board, as you ride out the wave to shore.

My own experience using MBRE

I have specialized in alcohol/drug counseling for more than 30 years, and I am very excited about the many ways meditation and mindfulness can be used as a recovery enhancement for alcohol/drug addiction. In the last two years I have been introducing meditation and mindfulness practices in my two outpatient (alcohol/drug recovery) therapy groups, and have seen firsthand the many benefits of meditation and mindfulness practices in helping my clients to be more aware, compassionate to others and themselves and enjoying life more. I have seen remarkable growth in my group members, especially in their ability to be less reactive and more reflective.

The benefits of meditation and mindfulness include helping the individual to: have a “quality of calm awareness”; be less reactive and more reflective; reduce stress; learn how to enjoy life “in the now”; see the “joy” and “abundance” in his or her own life; have a stronger spiritual well-being; be compassionate to self and others; make connections and have interdependence; feel worthwhile; and no longer need to be in the “land of hungry ghosts.”

Richard Fields, PhD is the author of the college textbook Drugs in Perspective, 7th edition, and Awakening to Mindfulness: 10 Steps for Positive Change. He is a national trainer and consultant in the field of alcohol/drug recovery and mindfulness-based recovery enhancement (MBRE), the owner/director of FACES Conferences (www.facesconferences.com) and has a private counseling practice in Bellevue, Wash.

References

Bien, Thomas & Bien, Beverly (2002). Mindfulness Recovery — A Spiritual Path to Healing from Addiction, Wiley, N.Y.
Bien, Thomas & Bien, Beverly (2003). Finding the Center Within — The Healing Way of Mindfulness meditation. Wiley, N.Y.
Bowen, Sarah, Witkiewitz, Katie, Dillworth, Tirara & Marlatt, G. Alan (2007) “The role of Thought suppression in the relationship between mindfulness, meditation, and alcohol use.” Addictive Behaviors 32, 2323-2328.
Brazier, David (1997) The Feeling Buddha: A Buddhist Psychology of Character, Adversity, and Passion. Fromm International, New York.
Chodren, Pema (2001) The Places that Scare You: A Guide to Fearlessness in Different Times. Shambhala Publications, Boston.
Chodren, Pema (2005) When Things Fall Apart: Heart Advice for Difficult Times. Shambhala Publications, Boston.
Epstein, Mark (1998) Going to Pieces Without Falling Apart: Lessons from Meditation and Psychotherapy. Broadway Books, New York.
Fields, Richard (2008) Minestrone for the Mind, Awakening to Mindfulness, 10 Steps for Positive Change. Health Communications, Deerfield Beach.
Griffin, Kevin (2004) One Breath at a Time, Buddhism and the Twelve Steps. St. Martin’s Press,
Kornfield, Jack (1993) A Path with Heart: A guide Through the Perils and Promises of Spiritual Life. Bantam, New York.
Kornfield, Jack (2008). The Wise Heart — A Guide to the Universal Teachings of Buddhist Psychology. Bantam, New York.
Marlatt, G. Alan (2002) “Buddhist Psychology and the Treatment of Addictive Behavior.” Journal of Cognitive and Behavioral Practice 9(1) (2002): 44-49.
Marlatt, G. Alan & Chawla, Neharika (2007) “Meditation and Alcohol Use.” Southern Medical Journal. Vol. 100, no. 4.
Salzberg, Sharon (1990) Lovingkindness:The Revolutionary Art of Happiness. Shambhala, Boston.

This article is published in Counselor, The Magazine for Addiction Professionals, April 2009, v.10, n.2, pp.40-44.

Opioid-Withdrawal in Hepatitis C. Patients

Researchers at the University of Pennsylvania have demonstrated that morphine withdrawal complicates hepatitis C by suppressing IFN-alpha-mediated immunity and enhancing virus replication. The paper by Wang et al., �Morphine withdrawal enhances hepatitis C virus (HCV) replicon expression,� appears in the November issue of The American Journal of Pathology and is accompanied by a commentary.

Hepatitis C virus (HCV) is common among intravenous drug users, with 70 to 80% of abusers infected in the United States. This high association has peaked interest in determining the effects of drug abuse, specifically opiates, on progression of the disease. The discovery of such an association would impact treatment of both HCV infection and drug abuse.

Dr. Wen-Zhe Ho has been interested in such interplay for some time. His laboratory has previously shown using cell culture that morphine enhances virus replication and inhibits IFN-alpha (a natural anti-viral factor produced by immune, as well as host cells, and the only one approved in recombinant form for treating HCV infection). To further these results, his lab has used a cell model system to determine the consequences of morphine withdrawal, which is a common recurring event in opioid users.

Chuan-Qing Wang and colleagues examined the effects of morphine withdrawal (MW) on HCV-infected cultured liver cells by exposing cells to the drug for four days followed by its removal. They also assessed the effects of using naloxone, to block the opioid receptors, in conjunction with drug removal, i.e. precipitated morphine withdrawal (PW). To measure HCV replication, they used a virus-like �replicon� that mimics the events that occur in liver cells and expression of viral RNA and proteins that HCV uses. Although the replicon does not produce the infectious virus, the HCV replicon system represents the best available system for examining the impact of opiates on HCV at the time of their research study.

Similar to their previous results, the authors found that MW and PW increased levels of HCV replicon RNA and protein expression. In addition, both withdrawal scenarios inhibited IFN-alpha expression in liver cells in the presence or absence of HCV replicon. Since IFN-alpha is a critical self-defense mechanism utilized by liver cells to fight off viral infection, including HIV, this study suggests that morphine withdrawal weakens host cell immunity and provides a favorable environment for HCV growth in the liver.

The authors extended their study by examining the mechanism behind these observations. MW and PW inactivated the IFN-alpha promoter (the switch for making IFN-alpha) by directly inhibiting its activator, interferon regulatory factor-7 (IRF-7), and this effect was more pronounced in HCV replicon-containing cells. Finally, the ability of IFN-alpha treatment to block HCV replicon expression (85%) fell following MW (60%) and PW (50%). This finding, in conjunction with the earlier report by the same group, provides an explanation to the question of why so many HCV-infected patients fail to respond to IFN-alpha treatment.

Although the clinical relevance of this study remains to be determined, these data showing that withdrawal promotes HCV expression by suppressing anti-HCV factor (IFN-alpha) production by liver cells suggests that �opioid abuse may contribute to the chronicity of HCV infection and promote HCV disease progression.� The study also underscores the necessity of future clinical and epidemiological studies to define the role of opiate abuse in promoting HCV disease.

These results suggest that opioid abusers experiencing periods of drug abuse, followed by periods of withdrawal (due to lack of supplies) may lead to immunocompromised liver. These findings further support the need for methadone maintenance treatment as an additional benefit for opioid abusers.

Research was supported by National Institute on Drug Abuse, National Institutes of Health.

This work involved collaborators at Joseph Stokes, Jr. Research Institute at The Children’s Hospital of Philadelphia; The Center for Studies of Addiction, University of Pennsylvania School of Medicine; and The Children’s Hospital of Fudan University, Shanghai, China.

Wang C-Q, Li Y, Douglas SD, Wang X, Metzger DS, Zhang T, Ho W-Z: Morphine withdrawal enhances hepatitis C virus (HCV) replicon expression. Am J Pathol 2005, 167:1333-1340

The American Journal of Pathology, the official journal of the American Society for Investigative Pathology (ASIP), seeks to publish high-quality original papers on the cellular and molecular mechanisms of disease. The editors accept manuscripts which report important findings on disease pathogenesis or basic biological mechanisms that relate to disease, without preference for a specific method of analysis. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, biological, animal, chemical and immunological approaches in conjunction with morphology.

ntravenous (IV) drug users who abuse morphine, then withdraw from it later, may be unknowingly complicating the beneficial effects of their hepatitis C treatment or giving their hepatitis infection an unwanted boost. That’s the conclusion of a study by researchers at Children’s Hospital of Philadelphia, the University of Pennsylvania and in China.1 The findings are published in the November issue of the American Journal of Pathology.
Detrimental Effects of Morphine Withdrawal
Quitting morphine in this population of hepatitis C patients may suppress the benefits of interferon-alfa in the body and enhance the replication of the virus, the study investigators led by Wen-Zhe Ho, MD, a research associate professor in the division of Immunologic and Infectious Diseases at Children’s Hospital of Philadelphia, reported.
According to the study investigators, hepatitis C infection is common among IV drug users; up to 90 percent of such users are infected with HCV in the United States, and one-fifth to one-half have chronic infection.2 The high numbers of these patients with the disease has prompted medical researchers to study the effects of drug abuse, especially the use of opiates, on HCV progression.
„In the case of HCV infection, there is little information about whether drug abuse, such as heroin, enhances HCV replication and promotes HCV disease progression,“ wrote Ho and his team. „This lack of knowledge about the impact of opioid abuse on HCV disease is a major barrier to fundamental understanding of HCV-related morbidity and mortality among intravenous drug users and to the development of new therapeutic approaches for HCV infection.“
The scientists theorized that illicit drugs might be able to detrimentally alter the immune response against the viral infection in some way. Other studies, they pointed out, showed that these drugs have the ability to block the production of beneficial interferons in the body that normally fight the virus.

Morphine’s Effect on Hepatitis C Studied Previously
In a previous study, Ho and his colleagues found that morphine boosted the virus‘ growth and interfered with interferon alfa in a collection of liver cells.3 Interferon alfa is the basis for the pegylated interferon that people with hepatitis C take as medication for the disease today in combination with the antiviral oral drug, ribavirin.4 Also produced naturally in the body, interferon is an antiviral factor produced by certain cells.
The follow-up to that laboratory-based study was the latest research aimed at determining how withdrawing from morphine might affect the course of the disease. „Physical dependence on morphine is characterized by the occurrence of an abstinence or withdrawal syndrome on termination of the drug,“ wrote Ho and his fellow investigators. These abstinence syndromes also can occur during the use of an opioid antagonist such as naloxone (Narcan), a drug that reverses the effects of narcotics, the researchers explained. Thus, they also tested the effect of naloxone-induced morphine withdrawal for the study.
Ho and his team exposed a group of liver cells kept in culture to morphine for four days, then removed it. The scientists also used a model that mimicked the events that occur in liver cells when genetic material (HCV RNA) and proteins used by the hepatitis C virus to create infection are present. This allowed the researchers to mimic the replication patterns of the virus without actually using an infectious virus.
Effects of Morphine Withdrawal
Similar to what they found in their previous study,3 Ho and his colleagues learned that removing morphine boosted levels of HCV RNA (the genetic material used by the virus) and hepatitis C viral protein in the cells. This, in essence, indicates that the viral infection is spreading. However, 72 hours after morphine was removed, HCV RNA levels decreased, suggesting there was only a temporary surge.
Withdrawing the morphine also blocked interferon-alfa production in the liver cells compared to cells in which morphine was not withdrawn. Since interferon-alfa is a critical self-defense mechanism used by liver cells to fight off attacks by the hepatitis C virus or HIV, the findings suggest that drug abusers who quit using morphine can weaken their immune system’s ability to defend the body against an HCV infection, and provides a favorable environment for hepatitis C viral growth in the liver.
Underlying Causes Studied
Next, Ho’s group wanted to understand why removing morphine created such a beneficial environment for the hepatitis C virus. They learned that removing morphine from liver cells blocked the production of interferon-alfa by, in turn, suppressing its activator, interferon regulatory factor-7 (IRF-7). The team also found that the ability of interferon-alfa to block HCV replication (or the model of HCV in this case) fell by nearly two-thirds.
The same detrimental effect of morphine removal also occurred in relation to manmade interferon alfa. This manmade, or recombinant, form is similar to the interferon medication used for people with hepatitis C today. When synthetic interferon was added to the cell lines, they demonstrated a strong ability to fight off the hepatitis virus. However, when morphine was withdrawn from the cells, the anti-HCV ability of interferon-alfa „was significantly diminished,“ Ho and his colleagues wrote.
These results were observed when morphine was directly withdrawn or indirectly removed by using naloxone, they reported, and even to a greater extent in the latter case.
„Collectively, these new observations in conjunction with our earlier findings support the notion that opioid abuse is a co-factor that promotes HCV replication,“ wrote Ho and his colleagues.
The researchers point out that the clinical relevance of this study remains to be determined, but the findings suggest that „opioid abuse may contribute to the chronicity of HCV infection and promote HCV disease progression.“
They recommend both clinical and epidemiological studies be launched to better define the rule of drug abuse in the context of HCV infection. In the meantime, they say drug abusers who use such opioids as morphine, followed by periods of withdrawal due to lack of supplies, may be doing much more harm to their livers.
„Our findings provide a plausible interpretation of the high failure rate of interferon-alfa therapy in intravenous drug users,“ the investigators concluded. „The identification of mechanism(s) involved in morphine’s action on the anti-HCV effect of interferon-alfa has the potential to improve interferon-alfa-based treatment for HCV-infected IV drug users.“
Study Reaction
In an accompanying editorial,5 Kevin Moore, PhD, and Geoff Dusheiko, MD, both professors of Hepatology at Royal Free and University College Medical School in London, write that the findings suggest that IV drug abusers or those receiving opioid substitutes like methadone, and who are infected with HCV, may have more difficulty clearing the virus.
„Until recently, there were no data on the effects of opiates on HCV replication or the development of liver injury and fibrosis, one of the earliest features of progression to cirrhosis,“ wrote Moore and Dusheiko.
„The growing implication from these and other studies is that continued opiate abuse leads to enhanced viral replication, liver injury, and … fibrosis. Further studies are required to determine whether these effects occur in humans, as well,“ they wrote.

The incentive sensitization theory of addiction:

We present a brief overview of the incentive sensitization theory of addiction.

This posits that addiction is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems
that attribute incentive salience to reward-associated stimuli. If rendered hypersensitive, these
systems cause pathological incentive motivation (‘wanting’) for drugs. We address some current
questions including: what is the role of learning in incentive sensitization and addiction? Does
incentive sensitization occur in human addicts? Is the development of addiction-like behaviour in
animals associated with sensitization? What is the best way to model addiction symptoms using
animal models? And, finally, what are the roles of affective pleasure or withdrawal in addiction?

1. INTRODUCTION
At some time in their life, most people try a potentially
addictive drug (e.g. alcohol). However, few become
addicts. Addiction implies a pathological and compulsive
pattern of drug-seeking and drug-taking behaviours,
which occupies an inordinate amount of an individual’s
time and thoughts, and persists despite adverse
consequences (Hasin et al. 2006). Addicts also find it
difficult to reduce or terminate drug use, even when
they desire to do so. Finally, addicts are highly
vulnerable to relapse even after long abstinence and
well after symptoms of withdrawal have disappeared.
Thus, a key question in addiction research is: what is
responsible for the transition to addiction in those few
susceptible individuals?
Over the last 20 years or so there has been increasing
recognition that drugs change the brain of addicts in
complex and persistent ways, so persistent that they
far outlast other changes associated with tolerance
and withdrawal. It is important to identify the brain
changes that cause the transition to addiction from
casual or recreational drug use, and the features that
make particular individuals especially susceptible to the
transition (Robinson & Berridge 1993; Nestler 2001;
Hyman et al. 2006; Kalivas & O’Brien 2008). Persistent
drug-induced changes in the brain alter a number of
psychological processes, resulting in various symptoms
of addiction. We suggested in the incentive sensitization
theory of addiction, originally published in
1993, that the most important of these psychological
changes is a ‘sensitization’ or hypersensitivity to the
incentive motivational effects of drugs and drug-associated
stimuli (Robinson & Berridge 1993). Incentive sensitization
produces a bias of attentional processing
towards drug-associated stimuli and pathological
motivation for drugs (compulsive ‘wanting’). When
combined with impaired executive control over
behaviour, incentive sensitization culminates in the
core symptoms of addiction (Robinson & Berridge
1993, 2000, 2003). Incentive sensitization has drawn
considerable interest in the past 15 years and, therefore,
we thought it worthwhile to update our perspective.
We present here a brief and idiosyncratic overview
of this view of addiction and raise some current issues

2. WHAT IS INCENTIVE SENSITIZATION THEORY
AND WHAT IS THE ROLE OF LEARNING?
The central thesis of the incentive sensitization theory
of addiction (Robinson & Berridge 1993) is that
repeated exposure to potentially addictive drugs can,
in susceptible individuals and under particular circumstances,
persistently change brain cells and circuits
that normally regulate the attribution of incentive
salience to stimuli, a psychological process involved in
motivated behaviour. The nature of these ‘neuroadaptations’
is to render these brain circuits hypersensitive
(‘sensitized’) in a way that results in pathological levels
of incentive salience being attributed to drugs and
drug-associated cues. Persistence of incentive sensitization
makes pathological incentive motivation
(wanting) for drugs last for years, even after the
discontinuation of drug use. Sensitized incentive
salience can be manifest in behaviour via either implicit
(as unconscious wanting) or explicit (as conscious
craving) processes, depending on circumstances.
Finally, the focus on drugs in particular in addicts is

produced by an interaction between incentive salience

mechanisms with associative learning mechanisms that
normally direct motivation to specific and appropriate
targets. Learning specifies the object of desire, but it is
important to note that learning per se is not enough for
pathological motivation to take drugs. Thus, we argue
that pathological motivation arises from sensitization of
brain circuits that mediate Pavlovian conditioned
incentive motivational processes (i.e. incentive sensitization).
However, it is important to emphasize that
associative learning processes can modulate the
expression of neural sensitization in behaviour at
particular places or times (and not others), as well as
guide the direction of incentive attributions. This is why
behavioural sensitization is often expressed only in
contexts in which the drugs have previously been
experienced (Stewart & Vezina 1991; Anagnostaras &
Robinson 1996; Robinson et al. 1998), and may
reflect the operation of an ‘occasion-setting’ type of
mechanism (Anagnostaras et al. 2002). Learning might
be viewed as layered onto basic sensitization processes
in a top-down fashion, similar to how learning regulates
the expression of such non-associative motivation
processes as stress and pain. The contextual control
over the expression of sensitization provides an
additional mechanism that accounts for why addicts
‘want’ drugs most particularly when they are in drugassociated
contexts.
Finally, by spreading beyond the associative focus of
wanting on drug targets, incentive sensitization can also
sometimes spill over in animals or humans to other
targets, such as food, sex, gambling, etc. (Mitchell &
Stewart 1990; Fiorino & Phillips 1999a,b; Taylor &
Horger 1999; Nocjar & Panksepp 2002). For example,
treatment with dopaminergic medications in some
patient populations can lead to a ‘dopamine dysregulation
syndrome’ (DDS) that is manifest not only by
compulsive drug use but also sometimes by ‘pathological
gambling, hypersexuality, food bingeing . and
punding, a form of complex behavioral stereotypy’
(Evans et al. 2006, p. 852).
(a) Incentive sensitization: more than just
learning
It has become popular to refer to addiction as a ‘learning
disorder’ (Hyman 2005), but we think that this phrase
may be too narrow to fit reality. Learning is only one
part of the process and probably not the one that
contributes most to the pathological pursuit of drugs.
The most influential type of ‘learning hypothesis’
suggests that drugs promote the learning of strong
‘automatized’ stimulus–response (S–R) habits, and it is
then supposed that by their nature S–R habits confer
compulsivity to behaviour (Tiffany 1990; Berke &
Hyman 2000; Everitt et al. 2001; Hyman et al. 2006).
However, it is difficult to imagine how any influence
of drugs on learning processes alone could confer
compulsivity on behaviour, unless an additional
motivational component was also involved, and S–R
habits by definition are not modulated by motivational
factors (Robinson & Berridge 2003). Do automatic
S–R habits really become compulsive merely by virtue
of being extremely well learned? We have doubts.
Strong S–R habits do not necessarily lead to compulsive
behaviour: activities such as tying shoes, brushing
teeth, etc. are not performed compulsively by most
people, even after being performed more than 10 000
times. Additional motivational processes seem needed
to explain why an addict waking up in the morning with
no drug spends the day engaging in a complex and
sometimes new series of behaviours, such as scamming,
stealing and negotiating, all seemingly motivated
to procure drug. Addicts do what they have to do and
go where they have to go to get drugs, even if actions
and routes that have never been performed before are
required. Such focused yet flexible behaviour in
addiction shows pathological motivation for drugs
that cannot be explained by evoking S–R habits.
Indeed, a strict S–R habit theory would require the
addict, upon waking up in the morning with no drug
available, to engage ‘automatically’ in exactly the same
old sequence of habitual actions they used previously to
get drugs, whether the actions were currently effective
or not. Yet addicts in the real world are not S–R
automatons; they are, if nothing else, quite resourceful.
On the other hand, everyone must agree that S–R
habits probably contribute to the automatized
behaviours and rituals involved in consuming drugs
once obtained (Tiffany 1990), and it has been shown
that treatment with drugs facilitates the development
of S–R habits in animals (Miles et al. 2003; Nelson &
Killcross 2006), perhaps via recruitment of the dorsal
striatum (Everitt et al. 2001; Porrino et al. 2007). We
also note that habits may be especially prominent in
standard animal self-administration experiments,
where only a single response is available to be
performed (e.g. press a lever) thousands of times in a
very impoverished environment to earn injections of
drugs. Thus, we think studies on how drugs promote
the learning of S–R habits will provide important
information about the regulation of drug consumption
behaviour in addicts, but this is not the core problem
in addiction.
(b) Relation of incentive sensitization to cognitive
dysfunction
The incentive sensitization theory focuses on sensitization-
induced changes in incentive motivational processes
and related changes in the brain, but we have
acknowledged that other brain changes contribute
importantly to addiction too, including damage or
dysfunction in cortical mechanisms that underlie cognitive
choice and decision making (Robinson & Berridge
2000, 2003). Many studies have documented that
changes in ‘executive functions’, involving howalternative
outcomes are evaluated and decisions and choices made,
occur in addicts and animals given drugs (Jentsch &
Taylor 1999; Rogers & Robbins 2001; Bechara et al.
2002; Schoenbaum & Shaham 2008). We agree that the
impairment of executive control plays an important
role in making bad choices about drugs, especially when
combined with the pathological incentive motivation
for drugs induced by incentive sensitization.

CONCLUSION
In conclusion, addiction involves drug-induced
changes in many different brain circuits, leading to
complex changes in behaviour and psychological
function.We have argued that the core changes leading
to addiction occur when incentive sensitization
combines with defects in cognitive decision making
and the resulting ‘loss of inhibitory control over
behaviour and poor judgement, combined with sensitization
of addicts’ motivational impulses to obtain
and take drugs, makes for a potentially disastrous
combination’ (Robinson & Berridge 2003, pp. 44–46).
Thus, bolstered by the evidence that has accumulated
over recent years, we remain confident in concluding
‘that at its heart, addiction is a disorder of aberrant
incentive motivation due to drug-induced sensitization
of neural systems that attribute salience to particular
stimuli. It can be triggered by drug cues as a learned
motivational response of the brain, but it is not a disorder
of aberrant learning per se. Once it exists, sensitized
wanting may compel drug pursuit whether or not an
addict has any withdrawal symptoms at all. And
because incentive salience is distinct from pleasure or
liking processes, sensitization gives impulsive drug
wanting an enduring life of its own’ (Robinson &
Berridge 2003).

For further information:Addiction_Theory2

World-Hepatitis Day (19.05.10)

World Hepatitis Day: Will CA Allow Pharmacists to Save Lives and Money through Syringes?

California is one of only three states in the U.S. that still prohibits pharmacists from selling a syringe without a prescription from a physician.

May 19th marks World Hepatitis Awareness Day – a great opportunity for California to take action to help prevent liver cancer and liver disease caused by hepatitis C and B. We ask you to join us in supporting Senate Bill 1029 to ensure all Californians have access to an essential and common-sense component of an effective hepatitis prevention strategy: the ability to purchase sterile syringes in a pharmacy.

Hepatitis C, which is commonly transmitted when syringes are shared, can lead to liver disease, cirrhosis, liver cancer, and premature death. While treatment for hepatitis C is partially effective, it is expensive and for some patients debilitating. Even with treatment, some remain chronically infected.

Long after a person has stopped using drugs, living with chronic hepatitis C can lead to other health problems, to disability, to job loss, and even homelessness. Thirty percent of people living with HIV are co-infected with hepatitis C. Hepatitis C is now one of the leading causes of death for people with HIV/AIDS in San Francisco. Hospitalizations for hepatitis C cost the California taxpayers over $1.5 billion in 2007 alone.

While all forms of hepatitis can cause severe health problems and even death, there is no vaccine for hepatitis C. The only way to prevent it is to ensure that people have the information and resources they need to avoid transmitting it.

Yet California is one of only three states in the U.S. that still prohibits pharmacists from selling a syringe without a prescription from a physician. Most states amended their laws in light of evidence that limited accesses to sterile syringes led drug users to share used ones, and that sharing syringes transmits HIV and hepatitis B and C.

The sharing of used syringes is the most common cause of new hepatitis C infections in the state and the second most common cause of HIV infection. We know from the research that pharmacy sales are a cost-effective way to combat the spread of hepatitis C and HIV without contributing to increased drug use, drug injection, crime or unsafe discard of syringes.

That is why Senate Bill 1029 is needed. It would expand the current pilot program, scheduled to end this year, to allow any pharmacy in the state to sell up to 30 syringes to individuals if the pharmacist so desires. Study after study has shown that increasing access to sterile syringes is the best way to prevent syringe sharing. By preventing HIV and hepatitis C, it is an efficient and cost-effective means of saving public dollars, and more importantly, lives. There is no cost to taxpayers through this plan, as the cost of prevention falls to the individual who purchases the syringes.

As people concerned with the health and well-being of all Californians, we ask you to stand with us in support of SB 1029. The California Department of Public Health, the Federal Centers for Disease Control & Prevention, the World Health Organization, and all leading health policy research organizations agree – safe and legal syringe access through pharmacies is a key component to the prevention of hepatitis C and HIV.
Leland Y. Yee, Ph.D. (D-San Francisco) is a California state Senator. Barry Zevin MD, is a physician specialist with the, Tom Waddell Health Center, San Francisco Department of Public Health, and assistant clinical professor at UCSF School of Medicine.

source: http://www.alternet.org/health/14690…rough_syringes

Hepatitis C can lie low for years until it wreaks havoc with your liver

WHO’S AT RISK
Hepatitis C is a disease of the liver; there are five hepatitis viruses, and this one has one of the highest rates of progression to chronic disease. “Hepatitis C is a viral infection that causes inflammation of the liver that can lead to increased scar tissue and eventually to cirrhosis,” says Kim-Schluger. “About 4 million Americans are infected with hepatitis C — 1.6% of the population.”

Hepatitis C is a blood-borne disease whose underlying virus was only isolated in 1989. “If you look the number new infections through the decades, a large percentage of patients were infected before 1992, when we developed a good test for hepatitis C,” says Kim-Schluger. “Infection rates dropped precipitously after that.” Because the blood supply wasn’t being reliably screened for hepatitis C until 1992, many americans were infected as the result of blood transfusions.

The two groups at highest risk of the disease are people who received transfusions before 1992 and IV drug users. Other groups at risk are people who have used intranasal cocaine, hemodialysis patients, and health-care workers who are pricked by needles. The virus can also be sexually transmitted. “The risk increases with high-risk behaviors like multiple partners,” says Kim-Schluger. “It’s a low risk, but it’s not zero.”

SIGNS AND SYMPTOMS:
For many patients, the diagnosis of hepatitis C comes without warning signs. “The tricky thing is that the majority of people are asymptomatic, or only have vague symptoms like feeling fatigued,” says Kim-Schluger. “So it is up to the doctor to ask about the risk factors and then screen people who are at risk.”

Up to about 15% of people infected by the hepatitis C virus are able to clear it from their bodies spontaneously. “The other 85% will continue to have virus within their blood,” says Kim-Schluger. “Of that group, about 20% of will develop cirrhosis and 1% to 5% will develop liver cancer related to cirrhosis.” With an infected population of 4 million, these percentages indicate that there will be hundreds of thousands of cases of severe liver disease caused by hepatitis C in the next 10 to 20 years.

Hepatitis C usually has a long latency period, during which the virus lies dormant. “The delay between infection and end-stage liver disease varies a lot, depending on factors like when you were infected and your gender,” says Kim. “It’s usually about 30 years from infection to cirrhosis.” Using alcohol and marijuana shortens this lag. The disease also progresses faster in people who are older than 40 when they get infected. Premenopausal women are slightly protected by estrogen, which may slow fibrosis, the growth of damaging scar tissue in the liver.

Patients do start to show symptoms when they reach end-stage liver disease. “By this time, there is often bleeding in the esophagus or the stomach,” says Kim. “That has to do with the scar tissue causing increased pressure and causing portal hypertension” — high blood pressure in the portal vein, which serves the liver. Often, fluid builds up in the abdomen, and the liver stops clearing the toxins it can ordinarily remove.

TRADITIONAL TREATMENT
Hepatitis C isn’t treated until it becomes chronic, which means the body hasn’t cleared the virus on its own. “The first line of treatment is a combination of drug therapies,” says Kim. “Pegylated interferon is an injection that you get once a week, and ribavirin is a drug that you take every day.” Depending on the genetic makeup, or genotype, of the virus you have, the therapy lasts six to 12 months. right now, the success rate for these antiviral treatments is about 50%. “If the treatment is successful, it gets rid of the virus,” says Kim. “but it’s difficult treatment, and there are many side effects.”

Patients have three types of responses to the therapy. “Responders clear the virus, and nonresponders don’t clear it at all,” says Kim. “Relapsers clear the virus during therapy, but afterward it comes back.”

For patients whose hepatitis C progresses to cirrhosis and then end-stage liver disease, a transplant is the sole remaining option. “The only way to survive end-stage liver disease is a transplant, and the overall transplant survival rate after one year is 85%,” says Kim. “Unfortunately, the virus doesn’t go away after transplant, so there are issues of recurrent disease after transplant.” Beyond liver transplant, “the next step would be a cure, and I am hopeful that there will be a cure during our lifetime,” says Kim.

RESEARCH BREAKTHROUGHS:
Doctors are continually improving the treatments available for hepatitis C so they can bring relief to a higher percentage of patients. “There are new protease and polymerase inhibitors coming out in the near future, as soon as 2011-2012,” says Kim. “You have to use this therapy in conjunction with the interferon and ribavirin, but then it increases the response rate from 50% to 70%.”

QUESTIONS FOR YOUR DOCTOR:
If you’re diagnosed and need therapy, the key question to ask is, “What can I expect in terms of side effects?” Some of the best medications can cause psychiatric side effects, so it’s essential to talk to your doctor about your psychiatric history and any other medications or herbal supplements you’re taking. Another good question is, “What genotype of hepatitis do I have, and how does

that affect the outcome of therapy?” Your options will depend on which genotype you have.

WHAT YOU CAN DO
Get screened.
If you have risk factors for hepatitis C, find out if you have the infection.

source: http://www.nydailynews.com/lifestyle…er.html?page=1

Resources!

For more information on CAMH publications, educational resources and training programs, please visit www.camh.net and follow the links.

The following is a select list of resources from CAMH.

Methadone Saves Lives
The MethadoneSavesLives.ca website is a portal to a comprehensive range of information about opioid dependence and treatment that is written accessibly for clients and care providers. It provides the facts that both professionals and people living with opioid drug problems (and their family and friends) need to make informed decisions about MMT.

The site contains information about:

• where to find help and an MMT program
• different types of opioid drugs, including the “Straight Talk” and “Do You Know” pamphlet series
• online tutorials about addiction
• how to order or download copies of CAMH publications, such as the Methadone Maintenance Treatment: Client Handbook and Methadone Maintenance Treatment: A Community Planning Guide
• how to order other educational materials such as the Prescription for Addiction DVD and user’s guide.

The site also contains information on CAMH’s Opiate Dependence Treatment Interprofessional Education Program, which prepares physicians, pharmacists, nurses, counsellors and case managers to provide a comprehensive range of services for people with opioid dependence.

To explore the site, go to www.MethadoneSavesLives.ca.

Methadone Maintenance Treatment: A Community Planning Guide
Written by Mark Erdelyan, Senior Program Consultant, CAMH Windsor

This manual offers guidance to communities on how to educate community members about the benefits of MMT and to develop and integrate effective treatment services. It reviews the stages of:

• establishing a community working group
• engaging the community, and
• planning, implementing and evaluating an MMT program.

The resource provides practical suggestions on how to build public support and increase acceptance of those struggling with opioid dependence, through raising community awareness and acceptance of MMT services.

[For more information, search Education and Courses on www.camh.net.]

Methadone Maintenance Treatment: Best Practices in Case Management
Kate Tschakovsky, MSW, RSW, Project Co-ordinator, OpiATE Project, CAMH

The first evidence-based guide written for case managers working with MMT clients in Ontario, this book describes the case manager’s roles of co-ordination, counselling and advocacy at the hub of a circle of collaborative, professional care. It makes recommendations about what clinicians, the agencies they work for, policy-makers and funding bodies need to do to achieve and support best practice in case management. Many composite case studies, practice points and clients’ quotations illustrate the issues and how best practices apply in different clinical scenarios.

[For more information, search Education and Courses on www.camh.net.]

Conclusion: Beyond the recommendations!

Beyond the scope of this document, there are other topics related to methadone and the treatment of opioid dependence that are important and require future consideration. In particular, pharmacists providing methadone services for patients with pain outside an addiction context still require knowledge of methadone’s unique pharmacology, to protect against the risk of overdose, and knowledge of its potential for abuse, to protect against the risk of diversion. Also, buprenorphine is emerging in Ontario as an alternative medication for the treatment of opioid dependence. Buprenorphine has some unique pharmacological properties that positively impact clinical care (e.g., improved safety profile, potential for less than daily dosing). However, pharmacists must also understand its pharmacology to appropriately start a client on buprenorphine (i.e., induction strategies). This drug also has a risk for diversion. Clinical practice guidelines for buprenorphine are not yet available in Ontario. Future best practice documents for the treatment of opioid dependence should include both methadone and buprenorphine.

The purpose of this guide is to provide recommendations for enhancing pharmacy services in methadone maintenance treatment in Ontario at the pharmacy and system level. It addresses issues beyond the individual pharmacist, making recommendations related to the pharmacy environment, pharmacist education programs, accessibility of pharmacy services and research needs. Consideration and adoption of these recommendations by pharmacy managers, corporate executives, the Ontario College of Pharmacists, pharmacy educational institutions, research scientists, professional pharmacy organizations and the government would provide significant support to pharmacists to provide best practice methadone services, with the goal of enhancing safety and improving therapeutic outcomes for clients in MMT. The results of needed pharmacy practice–based research would help inform future best practice guides for pharmacists providing service for opioid-dependent clients.

Pharmacy environment and client perspectives!

These recommendations address the first three questions posed by the panel at the beginning of the development process:

• What knowledge and skills and attitudes do pharmacists need to provide optimal MMT services safely to opioid-dependent clients?
• What is required in the pharmacy practice environment to ensure optimal MMT services?
• What can MMT clients expect from the care they receive from pharmacists and pharmacy practice sites?

The panel recommends that:

4. Pharmacy managers/owners offering MMT services ensure that the pharmacy has a suitable private area for respectful dosing and confidential discussion with clients. [III]

5. Pharmacy managers/owners ensure that all staff (professional and non-professional) employ the same respectful, professional approaches and attitudes toward MMT clients as they would use toward any other client of the pharmacy. [III]

6. The pharmacy have a treatment agreement with every client who is beginning methadone maintenance treatment at the pharmacy. [IV]

7. Pharmacy managers/owners inform relief pharmacists or new pharmacists that the practice site offers MMT services so that the pharmacists can ensure they are adequately prepared to offer this service. [IV]

8. Pharmacy managers ensure that there is a good system for communication among pharmacists within their practice environment regarding clients’ treatment. [IV]

Accessibility of MMT pharmacy services

These recommendations address the fourth question posed by the panel at the beginning of the development process:

• What is needed to ensure that MMT pharmacy services are available across Ontario?

The panel recommends that:

9. The Ontario College of Pharmacists, in conjunction with a professional pharmacy organization or CAMH, develop a mechanism for tracking pharmacies providing MMT services throughout the province, with the objective of identifying areas where there is little or no access to service. [IV]

10. Researchers survey pharmacists, particularly those in under-serviced regions, for their views and concerns about participating or not participating in MMT provision, with the goal of finding ways to encourage pharmacies throughout Ontario to provide MMT services and to support those currently providing MMT services. [III]

11. Researchers study the efficacy of offering incentives to pharmacists in remote or under-serviced areas to begin a methadone practice. [III]

12. Researchers work with the Ontario Pharmacy Council or a professional pharmacy organization to investigate fair and equitable payment models for MMT pharmacy services. [III]

13. The Local Health Integration Networks and addiction and mental health networks in under-serviced regions encourage and support initiatives to increase MMT availability. Pharmacists in these areas can be invited to participate with other local health professionals, public health service providers and local hospitals to explore ways in which their communities could provide MMT dispensing and pharmacy services to people with opioid dependence. [IV]

14. Hospitals and other institutions (e.g., jails and prisons, long-term care facilities) ensure that they are able to meet the medication needs of persons maintained on methadone who are admitted to their facilities, and specifically that:

a. Pharmacists in these environments have the appropriate knowledge and skills to ensure safe provision of methadone services. [IV]

b. Pharmacists communicate and collaborate intraprofessionally during their mutual clients’ transitions into or out of institutions to ensure they have safe and uninterrupted access to methadone treatment. [IV]

c. These institutions provide access, monitoring and pharmacy care services for their clients on methadone as they would for any other client. [IV]

Pharmacist education in MMT

These recommendations address the first and fourth questions posed by the panel at the beginning of the development process:

• What knowledge and skills and attitudes do pharmacists need to provide optimal MMT services safely to opioid-dependent clients?
• What is needed to ensure that MMT pharmacy services are available across Ontario?

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]

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

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]

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]

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]

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

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]

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, inter-vention strategies to use with difficult patients, and concurrent disorders, to enhance pharmacists’ skills in dealing with opioid-dependent clients. [IV]

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]

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]

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]

Research in MMT pharmacy practice

These recommendations address all four questions posed by the panel at the beginning of the development process:

• What knowledge and skills and attitudes do pharmacists need to provide optimal MMT services safely to opioid-dependent clients?
• What is required in the pharmacy practice environment to ensure optimal MMT services?
• What can MMT clients expect from the care they receive from pharmacists and pharmacy practice sites?
• What is needed to ensure that MMT pharmacy services are available across Ontario?

In addition to recommendations #10, 11 and 12, the panel recommends that:

32. Scientists in Ontario develop a research program to investigate all aspects of pharmacy practice in MMT, including:

a. the effectiveness of different models of care (including those with pharmacists in community pharmacies and in clinic settings)

b. the impact of pharmacist interventions on client outcomes

c. pharmacoeconomic implications

d. factors that could affect community pharmacy capacity to accommodate MMT clients

e. possible ways to increase access to methadone pharmacy services in remote areas. [IV]

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.

Methadone Vs. Subutex/ Suboxone!

Very few studies have considered heroin users’ views on substitute prescribing, in
particular with regards to subutex. The aim of this study was to conduct detailed
qualitative analysis, using the Grounded theory approach, on heroin users’ views on
substitute prescribing, paying specific attention to methadone and subutex. Semistructured
interviews were conducted with nine subjects recruited from an
abstinence-based, structured day care treatment program. All of the subjects were
either currently on a subutex prescribing program, or had remained abstinent from
illicit substances following the completion of a subutex treatment program. Five major
themes emerged from the analysis. These were reasons for obtaining a methadone
prescription, experiences with methadone programs, views on methadone, views on
subutex and views on an ideal opioid treatment program. Most of the findings were
supported by previous qualitative studies such as that of Neale (1999a) and Fischer
and colleagues (2002). However, there does appear to be some discrepancies
between qualitative and quantitative research with regards to consumer satisfaction
of methadone, in comparison to subutex, as a substitute drug. This study clearly
highlights the need for further research into users’ views on substitute prescribing,
with emphasis being placed on qualitative research considering users’ experiences
with subutex.

Read the full File: methadoneversussubutex kopie

Alcohol or Benzodiazepine Use in Methadone Patients: Is It Safe?

If a patient is stable on and tolerant to a maintenance dose of methadone, and has one alcoholic drink,* or takes a therapeutic, prescribed dose of alprazolam (Xanax) for panic disorder, would the combined effects cause a dangerous reaction? In either case, would the patient experience any greater effect from the drink or the therapeutic dose of alprazolam than would someone not on methadone? At what point — if any — do central nervous system (CNS) depressants have adverse effects on patients in opioid treatment programs (OTPs)? In January, AT Forum asked experts these questions, and found that in general, tolerance to a methadone dose means patients are not at increased risk when taking other CNS depressants — provided that the amounts of the other CNS depressants are not excessive.

There is no scientific evidence that people on stable doses of methadone shouldn’t have a cocktail or be prescribed a therapeutic dose of benzodiazepines, experts told AT Forum. The key is that the patient be tolerant to and not sedated by their methadone dose.

„We carried out many, many studies to address this, early on — whether or not any other CNS depressant potentiates the effect of methadone,“ says Mary Jeanne Kreek. MD, Head of the Laboratory of Biology of Addictive Diseases at The Rockefeller University in New York City. „The answer was absolutely not, until you got to very high doses of benzodiazepines or excessive amounts of alcohol.“

Dr. Kreek’s studies showed that „a normal social amount“ of alcohol would not affect the patient who is tolerant to methadone, any more than it would affect someone not taking methadone. This amount is no more than two or three drinks or maximally, four, she says.

Benzodiazepines — again, not in excess — also are safe. „A normal therapeutic dose of a benzodiazepine is not going to cause CNS depression in a stable OTP patient,“ says Dr. Kreek.

Tolerance Makes a Difference

For an opioid-naïve person, or a patient who is new or recently induced, and therefore not yet tolerant to or stabilized on methadone, combining methadone and other CNS depressants could be extremely dangerous. „If someone is opioid-naïve, takes even a small amount of methadone, and then drinks a glass of wine, the effect would cause the person to become sedated,“ says Ivan Montoya, MD, acting deputy director of the Division of Pharmacotherapies and Medical Consequences of Drug Abuse at the National Institute on Drug Abuse (NIDA). Slight increases could even cause overdose in the opioid-naïve patient. But there’s no important additive or synergistic effect for someone stabilized for years on a methadone dose, he says.

Should Methadone Doses Be Withheld?

Arriving at an OTP intoxicated on alcohol probably means the patient will have to wait a couple of hours before getting a full dose of methadone.

Clinicians who work with patients in medication-assisted treatment (MAT) prefer to „err on the side of caution,“ says Herbert Kleber, MD, professor of psychiatry at Columbia University in New York, where he is director of the division on substance abuse. Dr. Kleber, who developed the methadone program at Yale more than 50 years ago, strongly advises against giving methadone to a person who is intoxicated — not because there’s scientific proof that it should not be done, but because „it’s better to be safe than sorry — one always has to worry about the behavioral toxicity secondary to the alcohol intoxication.“

Dr. Kreek also agrees that intoxicated patients should not be given methadone immediately. „We recommend the patient be observed and not medicated until two hours later.“

There’s usually an interior waiting room where patients can sit and watch videos while waiting for the alcohol to wear off, says J. Thomas Payte, MD, medical director of the OTP chain Colonial Management Group. „When we see someone who is oversedated, we don’t know if the levels are going up or coming down,“ he says. Sometimes patients receive a partial dose, and the remainder a couple of hours later.

Edwin A. Salsitz, MD, addiction medicine specialist at Beth Israel Medical Center in New York City, would never give methadone to a patient who was intoxicated or sedated, if for no other reason than the patient might drive a car and cause an accident — with the chart clearly showing that the patient was given methadone (and the post-accident breath test showing a high level of alcohol). „There are legal reasons to worry about that,“ says Dr. Salsitz.

The Importance of an Adequate Methadone Dose

Still, Dr. Payte is concerned that some people may „overreact because of this theoretical additive effect.“ Alcohol or benzodiazepine use may indicate that a patient is not receiving an adequate methadone dose. „But people are afraid to raise the methadone dose, even if it’s indicated clinically, because of the bogeyman of interactions.“

In fact, patients may be using alcohol or benzodiazepines in an attempt to „boost“ the methadone dose, says Dr. Kreek.

The Need to Treat For All Substances of Abuse

Dr. Salsitz questions whether someone with opioid dependence should drink, even in small amounts. Patients might get a slight „buzz“ from alcohol — just as anyone would — and it might remind them of the days when they were using heroin and drinking, and lead to a relapse, he says. „It has nothing to do with synergy, it’s the risk of relapse.“

NIDA’s Dr. Montoya chastises OTPs that would treat someone with methadone for opioid addiction, but ignore their problems with benzodiazepines or alcohol. „You have to look at the signs and symptoms of the disease, and one of the symptoms is polysubstance abuse,“ he says.

Dr. Kleber agrees that it’s important to treat the whole patient. „Programs are trying to help the patient lead the best life possible,“ he says. But it’s also important not to lose sight of the fact that methadone is designed to treat opioid dependence — period.

An across-the-board ban on alcohol or benzodiazepines for all patients in MAT is not appropriate. But it’s also wrong to think patients on methadone can consume addictive substances any more safely than other people in recovery. And using excessive amounts of CNS depressants with methadone — even if the patient is tolerant to the methadone, and completely stable on it — is very dangerous, leading not only to sedation but possibly to an overdose as well, says Dr. Montoya.

If there is any doubt about whether an individual can limit alcohol consumption to two or three drinks, or take benzodiazepines only as prescribed, the risks from any interaction with methadone are too great.

* One drink is defined as 5 ounces of wine, 12 ounces of beer, or 1.5 ounces of distilled spirits. According to the National Institute on Alcohol Abuse and Alcoholism, more than 4 or 3 drinks a day or more than 14 or 7 a week constitute risky drinking for men and women, respectively.

Management of Hepatitis C (2002)

Introduction:
The hepatitis C virus (HCV) is one of the leading known causes of liver disease in the
United States. It is a common cause of cirrhosis and hepatocellular carcinoma (HCC) as well as
the most common reason for liver transplantation. At least 4 million people in this country are
believed to have been infected with HCV. Following the identification of hepatitis A and
hepatitis B, this disorder was categorized in 1974 as “non-A, non-B hepatitis.” In 1989, the
hepatitis C virus was identified and found to account for the majority of those patients with non-
A, non-B hepatitis. In March 1997, the National Institutes of Health (NIH) held a Consensus
Development Conference regarding management and treatment of HCV.

This led to an important, widely distributed NIH Consensus Statement that, for several years, defined the
standard of care. Now 5 years later, knowledge of hepatitis C has increased dramatically, leading
to the need to reexamine the approaches to management and treatment. This conference was
2
convened with the aim of reviewing the most recent developments regarding management,
treatment options, and the widening spectrum of potential candidates for treatment and of
updating the 1997 Consensus Statement.
This NIH Consensus Development Conference on Management of Hepatitis C: 2002 was
held June 10–12, 2002. The primary sponsors of this meeting were the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK) and the Office of Medical Applications
of Research (OMAR) of the NIH. The cosponsors were the National Institute of Child Health
and Human Development (NICHD); the National Cancer Institute (NCI); the National Center for
Complementary and Alternative Medicine (NCCAM); the National Institute on Alcohol Abuse
and Alcoholism (NIAAA); the National Institute on Drug Abuse (NIDA); the National Institute
of Allergy and Infectious Diseases (NIAID); the National Heart, Lung, and Blood Institute
(NHLBI); the Centers for Medicare & Medicaid Services (CMS); the Centers for Disease
Control and Prevention (CDC); the U.S. Food and Drug Administration (FDA); and the
U.S. Department of Veterans Affairs (VA).

The Agency for Healthcare Research and Quality (AHRQ) provided support to the NIH
Consensus Development Conference on Management of Hepatitis C: 2002 through its Evidencebased
Practice Center program. Under contract to the AHRQ, the Johns Hopkins University
Evidence-based Practice Center developed the systematic review and analysis that served as a
reference for discussion at the Conference.

This two-and-a-half-day conference examined the current state of knowledge regarding
the management of hepatitis C and identified directions for future research. During the first dayand-
a-half of the conference, experts presented the latest hepatitis C research findings to an
3 independent non-Federal Consensus Development Panel. After weighing this scientific evidence,
the panel drafted a statement, addressing the following key questions:
• What is the natural history of hepatitis C?
• What is the most appropriate approach to diagnose and monitor patients?
• What is the most effective therapy for hepatitis C?
• Which patients with hepatitis C should be treated?
• What recommendations can be made to patients to prevent transmission of
hepatitis C?
• What are the most important areas for future research?

Read the full statement:

NIH_HCV_Cons_2002Final

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

Naltrexone shortened opioid detoxification with buprenorphine

This double-blind, randomized, placebo-controlled clinical trial evaluated the impact on withdrawal symptoms of (i) combining naltrexone with a 4-day buprenorphine taper for short opioid detoxification (NB Group), compared to (ii) using a 4-day buprenorphine taper alone, followed by naltrexone on day 8 (PB Group). Sublingual buprenorphine was administered on days 1–4 (26 mg total).

For the NB Group (n=32) escalating doses of oral naltrexone were given on days 2–8 (placebo day 1). For the PB Group (n=28) placebo was given on days 1–7 and naltrexone on day 8. Main outcome measures were Observed Opioid Withdrawal scores (OOW, 0–30) and use of medications to treat opioid withdrawal. Of 32 patients in the NB group, 59% experienced clinically relevant withdrawal (defined as OOW≥5) on day 2, but, after day 5, none experienced withdrawal.

In the PB group, the number of patients experiencing withdrawal increased over time. The first naltrexone dose induced comparable withdrawal in both groups: peak OOW scores were (mean±SD) 5.2±3.3 on day 2 for the NB group, and 4.0±3.9 on day 8 for the PB group (NS), though, on day 2, 7 patients dropped out in the NB group and none in the PB group, while only one patient dropped out in the PB group on day 8. Throughout the 8-day study, patients in both groups received similar amount of adjunct medication: 0.64±0.07 mg (NB group) of clonidine vs 0.73±0.15 mg (PB group; NS). Only 25% of patients required use of sedatives (up to 20 mg diazepam). Starting naltrexone on day 2 appeared to abolish withdrawal symptoms after day 5 and, thus, to shorten the duration of withdrawal symptoms.

Peak withdrawal symptoms after naltrexone were of moderate intensity, suggesting that naltrexone combined with buprenorphine is an acceptable and safe treatment for shortened opioid detoxification and induction of naltrexone maintenance.

User perceptions of occasional and controlled heroin use

An exploration of heroin use among non-dependent and controlled dependent heroin users who saw their use as relatively problem-free.

Little is currently known about groups of occasional and controlled heroin users. This study aims to improve our understanding about patterns of heroin use, the nature of dependence and ways of controlling it.

The study describes how this largely hidden population maintained stable and controlled patterns of heroin use. Drawing on an internet survey of heroin users, followed by in-depth qualitative interviews, it examines their reasons for starting to use heroin, previous and current patterns of use, what helped to control use, and why they saw their use as fairly problem-free.

Heroin is a dangerous drug. It can have a devastating impact on individual lives, on users‘ families and on the wider community. However, as the report shows, some people, in some circumstances, can effectively manage and regulate their use. This raises important issues for treatment. Can dependent and chaotic heroin users learn from the experience of this group? Should controlled heroin use be regarded as an acceptable short- or middle-term goal for clients of drug treatment services? Should popular beliefs about the inherent uncontrollability of heroin dependence be left unchallenged?

The report deconstructs some of the myths surrounding heroin use and heroin dependence. It is relevant to policy-makers, those working in the drug treatment field, academics and drug researchers.

This is a massive File but interesting to read:1859354254

Similar Effects of Tramadol and Venlafaxine in Major Depressive Disorder

Abstract: The analgesic tramadol has many characteristics in common
with the antidepressant venlafaxine. The drugs are structurally
similar, share both serotonergic and noradrenergic properties, and
undergo a similar metabolic fate. In this study, a patient, who developed
significant depression following cessation of tramadol after
several years of therapy, is described. Her depression was then
treated with venlafaxine with excellent response. It appears that
tramadol may have provided a prophylactic antidepressant effect in
this patient. Because of its similarities to venlafaxine, tramadol may
possibly exert a degree of antidepressant effect in certain patients,
particularly those with chronic pain

Read more: Similar_effects_of_tramadol_and_venlafaxine_in_major_depressive_disorder

Europad 2010/03

Evaluation of Opioid-Dependent Prisoners in Oral Opioid Maintenance Therapy
Dose Determination in Dual Diagnosed Heroin Addicts during Methadone Treatment

Urine Labelling Marker System for Drug Testing Improves Patient Compliance
Quality of Life as a Means of Assessing Outcome in Opioid Dependence Treatment
Why There Has Been an Excess of Overdoses in Norway Since 1990

HeroinAddict1212010