Current and Experimental Therapeutics for the Treatment of Opioid Addiction

105 CURRENT AND EXPERIMENTAL THERAPEUTICS FOR THE TREATMENT OF OPIOID ADDICTION PAUL J. FUDALA GEORGE E. WOODY Currently, numerous effective pharmacologic and behav- ing treatment have been addicted to heroin or other opioids ioral therapies are available for the treatment of opioid ad- for 2 to 3 years, some for 30 years or more. Thus, treatment diction, and these two types of therapies often are combined usually involves changes in patients’ lifestyles. Although to optimize patient management. Newer therapeutic op- generally ineffective in producing sustained remission unless tions may take various forms. For example, methadone combined with long-term pharmacologic, psychosocial, or maintenance is an established treatment modality, whereas behavioral therapies, detoxification alone continues to be the use of buprenorphine and naloxone in an office-based widely used and studied. It is sometimes the only option setting represents a new variation on that theme. Clonidine available for patients who do not meet United States Food has been used extensively to ameliorate opioid withdrawal and Drug Administration (FDA) criteria for, do not desire, signs, whereas lofexidine is a structural analogue that ap- or do not have access to agonist medications such as metha- pears to have less hypotensive and sedating effects. The done or methadyl acetate (L-␣-acetylmethadol or LAAM). depot dosage form of naltrexone, currently under develop- The detoxification process may include use of opioid ment, may increase compliance with a medication that has agonists (e.g., methadone), partial agonists (e.g., buprenor- been an effective opioid antagonist but that has been un- phine), antagonists (e.g., naloxone, naltrexone), or nonopi- derused secondary to patient nonacceptance. In almost oid alternatives such as clonidine, benzodiazepines, or non- every treatment episode using pharmacotherapy, it is com- steroidal antiinflammatory agents. In many cases, one or bined with some type of psychosocial or behavioral treat- more medications are combined, such as naloxone with ment. Recent research has documented the value of these clonidine and a benzodiazepine. The choice of detoxifica- additional treatments and has provided insight into the ones tion medication and the duration of the process depend that are the most effective. This chapter reviews current on numerous factors including patient preference, clinician and experimental treatments for opioid addiction with an expertise and experience, type of treatment facility, li- emphasis on some of the newer, more promising, and inter- censing, and available resources. Ultimately, however, the esting therapies. goal of detoxification is the achievement (and maintenance) of a drug-free state while minimizing withdrawal. Unfortu- nately, however, detoxification for some patients appears to be used in a punitive manner or as an expedient means to TREATMENT PARADIGMS achieve a drug-free state rapidly with no follow-up pharma- Long-Term, Short-Term, Rapid, and cologic or behavioral therapy. Ultrarapid Opioid Detoxification Opioid detoxification paradigms are frequently catego- rized according to their nominal duration: long-term (typi- Detoxification from opioids, for most patients, is only the cally 180 days), short-term (up to 30 days), rapid (typically first phase of a longer treatment process. Most patients seek- 3 to 10 days), and ultrarapid (1 to 2 days). These temporal modifiers provide only a coarse description of the paradigm; they do not provide other important information such as Paul J. Fudala: Department of Psychiatry, University of Pennsylvania, the medications used or whether postdetoxification pharma- Philadelphia, Pennsylvania; Department of Behavioral Health Service, Veter- cologic (e.g., naltrexone maintenance), psychosocial, or be- ans Affairs Medical Center, Philadelphia, Pennsylvania. George E. Woody: Substance Abuse Treatment Unit, VA Medical Center, havioral therapy is provided. However, some general guide- Philadelphia, Pennsylvania. lines typically apply. 1508 Neuropsychopharmacology: The Fifth Generation of Progress The most common detoxification protocols, and those sible to know the overall effectiveness of this type of inter- for which the most data are available, are the long-term vention. (typically 180 days) and short-term (up to 30 days) para- A major concern regarding ultrarapid detoxification in digms involving the use of methadone. Unfortunately, these particular is the occurrence of potentially serious adverse strategies have not generally been associated with acceptable effects, such as respiratory distress (7), or other pulmonary treatment response using relapse to opioid use as an out- and renal complications (8), during or immediately after come criterion. For example, one study reported that more the procedure. A high frequency of vomiting has also been than half the patients participating in a 180-day detoxifica- reported (9). The degree to which serious adverse effects tion program were using opioids illicitly during the medica- occur has not yet been determined; however, there have tion-taper phase of the protocol (1). Six-month follow-up been press reports of sudden death occurring shortly after tested the procedure that were not caused by relapse to opioid use (26 ס indicated that 38.5% of the urine samples (n negative for illicit opioids, only three of 31 patients reported and overdose. remaining free of illicit opioids for the entire 6 months In spite of the emerging evidence about serious adverse before follow-up, and 22 participated in some other form effects, ultrarapid detoxification may be appropriate for of treatment (2). Results from more rapid detoxification highly selected patients based on considerations of previous evaluations using short- or even intermediate-term (up to treatment history, economic factors, and patient choice. 70 days) medication-tapering protocols are even less encour- However, patients seeking this treatment must be thor- aging and have an unfortunately low success rate. However, oughly informed that serious adverse effects, including sud- provision of additional services such as counseling, behav- den unexpected deaths, have occurred in association with ioral therapy, treatment of underlying psychopathologies, this procedure, and its use should probably be limited to job skills training, and family therapy to address concomi- inpatient settings where monitoring by anesthesiologists and other highly trained staff is available. tant treatment needs can improve outcome, although suc- ␮ cess rates remain low, even with these services (3). Buprenorphine, a -opioid partial agonist, has also been Rapid detoxification involves the use an opioid antago- used as a detoxification agent. Results from inpatient nist, typically naltrexone or naloxone, in combination with (10–12) and outpatient (13,14) studies have shown that it other medications (such as clonidine and benzodiazepines) is safe and well tolerated, and it mitigates opioid withdrawal to mitigate the precipitated withdrawal syndrome. The pro- signs and symptoms over a range of doses and detoxification schedules. Clonidine, an ␣ -adrenergic agonist, has been cedure is intended to expedite and compress the withdrawal 2 shown to suppress many of the autonomic signs and symp- process to minimize discomfort and to decrease treatment toms of opioid withdrawal. It can cause pronounced seda- time. Ultrarapid detoxification also uses other medications, tion and hypotension but has been used with few problems along with an opioid antagonist, to moderate withdrawal when appropriate monitoring is available. It does not sup- effects. However, rather than being awake as they are during press the subjective discomfort of withdrawal, and probably the rapid detoxification process, patients are placed under for that reason, it is not well accepted by most opioid ad- general anesthesia or, alternatively, are deeply sedated. A dicts. comprehensive review of the rapid and ultrarapid detoxifica- ␣ Other 2-adrenergic agonists have also been evaluated tion literature (identifying 12 and 9 of each type study, to find agents that are equally or more effective, but produce respectively) has been published (4). Rapid detoxification less sedation and hypotension than clonidine. Lofexidine, studies were conducted in inpatient facilities, outpatient a medication that was originally promoted as an antihyper- substance abuse treatment settings, and outpatient primary tensive, has been the most thoroughly studied. When com- care facilities; ultrarapid ones were confined to inpatient pared with clonidine, it was found to suppress autonomic settings. Patients included those who were heroin depen- signs and symptoms of opioid withdrawal equally, but with dent as well as those in methadone maintenance treatment. less sedation and hypotension (15–17). When compared Only four of the studies reviewed provided follow-up with methadone dose tapering, lofexidine detoxification was beyond the initial detoxification. Retention on postdetoxifi- associated with opioid withdrawal effects that peaked cation naltrexone maintenance in one rapid detoxification sooner, but resolved to negligible levels more rapidly (18). study was 53% at 1 month and 82% in another at 3 months. In another study (19), an accelerated 5-day lofexidine treat- Only one of the ultrarapid detoxification studies provided ment regimen attenuated opioid withdrawal symptoms follow-up information indicating that all patients (11 of 11) more rapidly than 10

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