Introduction: Setting the Stage — The Era of Medication-Assisted Treatment More than 50 million Americans are currently living with chronic pain unrelated to cancer. The costs associated with chronic pain are approximately 90 billion dollars annually. During the last two decades of the 20th century, there has been increased interest in support of fundamentally changing how physicians treat chronic pain conditions. Pressure from national agencies and worldwide organizations has led to amplified attention to untreated and undertreated pain symptoms. At the same time, pharmaceutical companies were marketing new products that were anticipated to be safer and to have lower dependence potential. In response, many physicians were enticed to prescribe opiates for patients with chronic noncancer pain (CNCP). By 2002, prescriptions for OxyContin alone had reached 6.2 million per year. Today, opiate analgesics are the most prescribed medication in the United States, and a clear reliance on prescribing these medications rather than getting to the underlying causes is now part of the standard for” pain management” medical practices. Not surprisingly, as rates of prescription opiates increase, so have the negative effects, including addiction and unintentional drug poisoning deaths. There is a close correlation between death and the amount of opiate medication sold. A recent study of the Treatment Episode Data Set (TEDS) revealed that admissions to substance abuse treatment programs for abuse of prescription pain relievers increased more than 400 percent. Prescription opiate abuse in the U.S. has overtaken illicit opiate (heroin) abuse and has grown to epidemic proportions. In spite of rising rates of nonmedical use of opiates (rates of nonmedical use of prescription pain relievers involve 5.2 million Americans), the medical field maintains that the potential for addiction is not sufficient to prohibit the use of narcotic medications. In February 2009, the American Pain Society and the American Academy of Pain Medicine published “Clinical Guidelines for the Use of Chronic Opiate Therapy in Chronic Noncancer Pain.”The guidelines offer clinical suggestions for appropriately managing pain while accounting for the risk of potential dependence. In addition to current prevention and awareness initiatives, national agencies such as the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) have also started to investigate the effectiveness of previous measures to curb misuse and abuse of opiate medication. Behavioral abuse and dependence patterns often develop during the course of prescribed treatment. Currently, many rehabilitation centers offer variable durations for detoxification, individual and group therapy, and recommendations for continuing care through such programs as Alcoholics Anonymous (AA) and Narcotics Anonymous (NA). However, with relapse rates so high, many clients have turned to medication-assisted treatment (formerly called maintenance) programs that provide long-lasting opiates, such as methadone (Dolophine) or buprenorphine (Suboxone and Subutex). Today, there are currently more than 1,000 clinics authorized to dispense Methadone and more than 1,800 treatment centers authorized to dispense buprenorphine in the U.S. This review will focus on the clinical uses, potential problems, and implications for treatment using buprenorphine. Basic Science and Pharmacology of Buprenorphine The U.S. Food and Drug Administration approved buprenorphine in 2002 for the treatment of opiate dependence. Under the Drug Addiction Treatment Act of 2000, buprenorphine is available for use through physicians registered with the Substance Abuse and Mental Health Administration (SAMSHA). There are currently more than 12,000 physicians waivered by the FDA to prescribe buprenorphine in a clinical office setting (SAMHSA, 2010). Buprenorphine’s unique pharmacology causes less of the same negative side effects commonly seen with morphine and methadone (e.g., respiratory depression, cognitive impairment, and euphoria more likely to be associated with craving and abuse) and has opened the way for treatment of opiate dependence in new settings. This allows treatment options to reach those who may not have previously had access or don’t feel comfortable with other treatment settings, such as a methadone clinic. Classified as a Schedule III narcotic, buprenorphine is a semi-synthetic opiate that is an antagonist at kappa-opiate receptor sites and a partial agonist of mu-opiate receptors. Activation of mu-receptors produces some of the most common effects associated with opiates, such as pleasure and pain relief. By not fully stimulating mu-receptors, the cognitive and euphoriogenic effects of buprenorphine are consequently not as intense as full agonist opiates, such as morphine or oxycodone. Buprenorphine is said to not provide the same levels of pleasure and positive mood elevation, nor to cause cravings as strong as commonly abused opiates, such as heroin, oxycodone, hydrocodone, morphine, and others. Due to its high affinity for mu-receptors, buprenorphine is not easily displaced and theoretically prevents the intense effects of other subsequently used opiates. In addition, it will dislodge a previously or presently used opiate from receptor sites, causing the user to withdraw abruptly from previously used opiates. Buprenorphine also has high affinity with kappa-receptors as an antagonist. Kappa-receptors have been shown to play a role in opposing the rewarding effects of drugs of abuse. By preventing the dysphoric effects of kappa-receptor stimulation, buprenorphine is able to elevate mood and to show antipsychotic properties. Blocking kappa-receptors may also contribute to buprenorphine’s analgesic properties. Buprenorphine has been touted as a safe, low-risk option for treatment of opiate dependence because of its mild effects and a ceiling effect at high doses. Yet, despite the apparent advantages of buprenorphine over other opiate maintenance medications, an abuse potential remains. Use of buprenorphine for diversion has been reported internationally. Also, using buprenorphine illicitly to avoid withdrawal symptoms (called “bridging”) until the drug(s) of choice become available is an alarming trend. Furthermore, when combined with benzodiazepines, there is an increased incidence of adverse effects including overdose and death. One new and dangerous trend is the rise of “user how-to” Websites touting the effects of “bupe”combined with promethazine, temgesic, hydroxyzine, and benzodiazepines as the “new heroin substitute.” Early development of buprenorphine has transferred from liquid injections (because of abuse potential), to sublingual solutions (because of practical limitations and limited oral bioavailability), and is now available in two forms of sublingual tablets. Tablets that contain only buprenorphine are marketed as Subutex. The risk potential for diversion remains with Subutex because tablets can easily be broken down, dissolved, and the solution injected. The second tablet form, Suboxone, was developed to incorporate naloxone (Narcan), a mu-opiate receptor competitive antagonist. Naloxone has low bioavailability when taken sublingually; however, when injected it produces a precipitated opiate withdrawal syndrome. The negative effects of the withdrawal syndrome are meant to deter intravenous abuse and have shown to be effective when compared to Subutex. Clinical Efficacy Studies — Detox and Maintenance Medication-assisted treatment programs that use methadone have been shown to reduce the spread of HIV, decreasing the use of illicit opiates and criminal activity, and prolonging average time until the next relapse . One of the most cited outcomes of buprenorphine maintenance is rates of treatment retention. Among combination treatment options, detoxification using buprenorphine and psychosocial treatments are more effective than use of pharmacological treatments alone and reflects established research indicating that the use or abuse of a substance implicates changes to more than just physiological processes. Buprenorphine for Pain: Does It Cause More Pain? Drug use has been positively correlated with pain tolerance and has been shown to vary depending on the type of drug used. Pain intolerance due to substance use may even appear to cause hyperalgesia in certain patients. Recovering drug addicts have shown higher levels of pain tolerance than their peers who are still using drugs, demonstrating that the hyperalgesic effects of opiates are drug- and dose-specific. In other words, opiates may cause more pain. Once the hyperalgesic effects begin to offset the analgesic properties of the prescribed opiate, pain treatment becomes more difficult. This inadvertent increase in pain tolerance hinders adequate pain management in patients with comorbid chronic pain conditions. This effect may not be as pronounced with patients receiving buprenorphine maintenance treatment versus treatment with full opiate agonists, but further research is needed to clarify the difference. Acute pain treatment can be hindered by the use of buprenorphine as well. Due to its pharmacological properties, emergency care centers may find it difficult to control acute pain if a patient is regularly taking buprenorphine. The effects of full agonist opiates will be blunted by the adherent buprenorphine molecule. Opiate tolerance also contributes to diminished pain relief as a result of the chronic use of a long-lasting opiate. Special consideration needs to be given to potential circumstances that patients taking buprenorphine may encounter during the course of their treatment. Where does that leave the addiction professional whose clients are on buprenorphine in his or her practice setting? Here are several key questions that will challenge each of us as we attempt to assess and treat opiate-dependent clients. Is the brain of the opiate addict more normal with buprenorphine than without, as many medication assistance proponents assert? At least with methadone-dependent addicts, it has been shown that brain dopamine transport system is impaired compared to abstinent opiate addicts. Is there a reasonable hope of achieving a buprenorphine-free state once it has been started? If so, when is the logical time to attempt withdrawal? After six weeks, six months, two years? If withdrawal fails, is that because of dependence on buprenorphine, which is extremely difficult to discontinue, or is relapse inevitable in the absence of some opiates? We all know that discontinuing maintenance doses of opiates is extremely difficult, but is that because of withdrawal (protracted with buprenorphine) or is it because the brain requires a medication like buprenorphine to function and feel normal? There are clinics that have sprung up in some cities that include buprenorphine treatment among a vast “service line”menu, including Botox, Restalyne, liposuction, and teeth whitening. Do we truly expect an addict to find recovery in such a setting? How are you to manage these clients as an addiction professional? It is your task to help clients find quality in their lives. Can you steer them to buprenorphine-friendly meetings? Should the maintained addict go to mainstream meetings and hide the fact that they are on buprenorphine? It is not uncommon for addicts who disclose their status to be ostracized or encouraged to discontinue medications by nonprofessional peers. Can you help clients navigate these difficult waters and develop a supportive community to help them as they live life on life’s terms? Some feel that opiate-free is simply not an achievable state; the data appears to suggest low percentages of successful abstinence. Where are all the addicts who are successful? There are thousands of opiate addicts in recovery who have abstained through the help of the 12-step fellowships for decades. We know it can be done, but how can we tell who is likely to be successful? Do we commit everyone to maintenance for life? Is this “harm reduction” or are we actually doing harm by using mediations for all without attempting to help clients achieve a drug-free state? Do we try abstinence a time or two or ten? Do we eventually accept buprenorphine-maintained recovery as a reasonable alternative? Do we try again for abstinence after a time? If so, when? These and other questions need to be studied in order for us to develop a rational policy for buprenorphine or opiate dependence and to provide the best care for all. Mel Pohl, MD, FASAM is the author of the following titles: References Alford, D., Compton, P., & Samet, J. (2006). Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Annals of Internal Medicine, 144, 127-134. Amato, L., Minozzi, S., Davoli, M., Vecchi, S., Ferri, M., & Mayet, S. (2009). 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