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Opioid maintenance, weaning and detoxification techniques: where we have been, where we are now and what the future holds

Practice Points

Anthony Plunkett*1, Devon Kuehn2, Mark Lenart3 & Indy Wilkinson2 „„ Opioid dependence and addiction are major problems worldwide. Addiction medicine is a complex field

of practice, requiring knowledge from a variety of specialties. „„ Detoxification, weaning and maintenance techniques are diverse; success varies on many factors,

including patient demographics, local culture and institutional protocols. „„ Traditional opioid substitution/detoxification techniques, such as methadone maintenance and slow

opioid taper, are common; however, newer, faster methods are being developed to minimize both cost and patient discomfort of withdrawal symptoms. „„ Protocols utilizing buprenorphine/naloxone combinations and ultra-rapid opiate detoxification allow

for accelerated treatment time frames that are measured in hours and days, instead of weeks to months. These two examples are very different treatment regimens, one utilizing inpatient admission and general anesthesia (ultra-rapid opiate detoxification), the latter utilizing medication management as an outpatient. „„ Complementary alternative medicine approaches, such as acupuncture, may have a role in opioid

weaning. „„ There is evidence that genetic variability is associated with addiction and substitution therapy. Continued

research in this area may lead to individualized approaches for opioid substitution, maintenance and weaning therapies.

SUMMARY Medically supervised opioid withdrawal is a complex and constantly evolving exercise in multimodal therapy that draws from the expertise of a variety of clinical specialties. Acute substitution and weaning has been performed utilizing opioid agonists, partial agonists (e.g.,  buprenorphine), mixed agonist/antagonists (e.g., Suboxone®), and a2  adrenergic agonists. While thousands of patients are being treated with these ‘classic’ opioid-withdrawal techniques, traditional treatment approaches are being challenged by the emergence of innovative techniques based on an understanding of the neuro­chemistry of addiction. Pharmacotherapy with controlled withdrawal is currently the most reliable Anesthesia & Operative Services, Acute Pain Medicine, Womack Army Medical Center, Fort Bragg, NC 28310, USA Womack Army Medical Center, Fort Bragg, NC 28310, USA 3 Naval Medical Center Portsmouth, 620 John Paul Jones Circle, Portsmouth, VA 23708-2197, USA *Author for correspondence: [email protected] 1 2

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special report  Plunkett, Kuehn, Lenart & Wilkinson method of opioid detoxification, but, as translational medicine continues to advance and genomic markers for opioid sensitivity and dependence are identified, the future shows great potential for growth and change. An estimated 9% of the US population is believed to have misused opioids, including illicit substances and prescription pain medications, over the course of their lifetimes [1]. Still greater, though, is the estimated number of patients who become physically dependent or addicted to opioids during the supervised management of acute or chronic pain [2,3]. For a variety of reasons, the course of patient care often involves decreasing the dose of or discontinuing opioids altogether. In physically dependent patients, withdrawal from opioids consistently produces a well-described constellation of uncomfortable and distressing symptoms. Due to these physiological alterations and the nature of the population, management of the opioid-dependent patient is a challenging exercise in multimodal therapy and polypharmacy, with inherent patient safety and medicolegal ramifications. A thorough understanding of tolerance, dependence and addiction is requisite when attempting to wean a patient from opioids. Tolerance is defined as the phenomenon by which a person requires an increased dosage of a medication to sustain a certain effect. It can be subdivided into two categories: the rapid onset tolerance to analgesia, and the slow developing tolerance to nonanalgesic CNS effects such as respiratory depression and nausea. Tolerance to opioid-induced constipation is controversial, but does not appear to reliably occur [4]. Opioid tolerance has been largely attributed to the upregulation of opioid receptors and their uncoupling from G-proteins with repeated agonism [5,6]. Opioids act on multiple receptor subtypes, each producing unique effects. As a result, physiologic tolerance to each effect occurs at a different rate. Physical dependence and addiction share many common traits but are not equivalent. Physical dependence is defined as an altered physiological state produced by repeated opioid administration. By contrast, addiction is the continued use of a mood altering substance or behavior despite adverse dependency consequences [7], or a neurological impairment leading to such behaviors. While both addiction and dependence are characterized by compulsive drug-seeking behavior; most opioid-addicted patients display some degree of physical dependence, the converse

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is not true [8]. The most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM V) further separates addiction from dependence. Addiction involves reward behavior and shows evidence of altered brain function and structure compared with those without addiction [9]. The basolateral amygdala is involved with hedonic responses and the reinforcement of use. A patient can be physically dependent on an opioid analgesic without being addicted. The term pseudo-dependence is used to describe drug-seeking behavior resulting from inadequate analgesia, which ceases once an efficacious dose is achieved. Immediately following the discontinuation of opioids in a physically dependant patient, the drug-to-receptor ratio begins to decline. As opioid levels drop below a threshold concentration, patients begin to manifest symptoms of physical withdrawal. The speed-of-onset of these symptoms correlates with the rate of drug dissociation from the receptor and underlying adaptation to chronic drug use. Duration of withdrawal symptoms also depends on both pharmacodynamic and pharmacokinetic factors. The type, quantity, frequency and duration of opioid use as well as patient variables such as hepatic and renal clearance, each contribute to opioid dissociation and elimination from the body. Each of these factors also impacts the onset and duration of withdrawal. Opioids with rapid elimination profiles are associated with shorter time intervals between timing of last opioid dose and onset of withdrawal symptoms, while those with longer elimination profiles manifest a relatively delayed development of symptoms. Symptoms of opioid withdrawal vary, but often include intense cravings, cramps, anxiety, nausea, vomiting and diarrhea. Rarely, if ever fatal, the severity of these symptoms, which range from mild discomfort to debilitating physiologic manifestations, is difficult to predict. Drugand patient-related factors have been analyzed in previous studies, but did not yield consistent results [10,11]. Opioid weaning can be defined as the process of medically supervised pharmacotherapy by which patients are allowed to withdraw from opioids in a controlled manner in order to achieve abstinence and physiologically normal

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Opioid maintenance, weaning & detoxification techniques  levels of functioning with minimal physical and emotional discomfort [12]. It should be noted, however, that some opioid-dependent patients can wean themselves from opioid use, without ever seeking medical supervision. In isolation, an acute phase of opioid detoxification, referred to as the detoxification–stabilization phase, is unlikely to achieve long-term recovery, and should be viewed as the initial preparation for continued multimodal treatment and rehabilitation [13,14]. Traditional acute detoxification pharmacotherapy involves agonist administration in progressively decreasing doses. The speed of agonist taper must be weighed against the patient’s level of withdrawal-associated discomfort. Though tapering rates vary by protocol, the primary determinant of success in an opioid detoxification program is patient adherence to the prescribed program. Due to a multitude of factors, not the least is the severity of withdrawal symptoms, attrition rates in both outpatient and inpatient opioid detoxification programs remain frustratingly high. A review of 218 international detoxification studies calculated the mean attrition rates for inpatient and outpatient opioid detoxification to be 25 and 65%, respectively, when using methadone and 28 and 47%, respectively when using a2 adrenergic agonists [15]. Studies seeking to identify risk factors for attrition from opioid detoxification programs have identified statistically significant demographic differences associated with education and marital status among adults [16]. Among youths, factors such as early adherence to the program and early negative urinalysis led to increased retention rates, while factors such as prior heroin use and hallucinogen use, tended to promote attrition [17]. In the adult population, having a lower level of education and being single were associated with higher attrition rates. The former finding is compatible with other studies relevant to the utilization of medical and psychiatric services [18,19]. This review will briefly discuss some common medical management techniques, as well as some of the more controversial accelerated techniques for opioid weaning. Substitution, weaning & withdrawal techniques Methadone is a synthetic, long-acting opioid that is an analog of morphine and heroin, thus mimicking their effects [20]. Developed in Germany in 1937, methadone was introduced in the USA in 1947 [21]. Oral doses of methadone

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can help stabilize opioid-dependent patients by mitigating opioid-withdrawal syndrome. At higher doses, it likely blocks the euphoric effects of these drugs, such that patients can eliminate use of morphine or heroin with minimal withdrawal side effects [22,23]. Methadone maintenance therapy (MMT) is utilized for patients who desire to abstain from illicit drug use but have a prior history of failing to do so. The length of treatment and the speed of reduction vary depending on the treating clinic, as well as on the patient. The goals of MMT include relief of narcotic craving, suppression of the abstinence syndrome, and blockade of the euphoric effects associated with opiates. MMT has been shown to be safe with long-term use, in addition, it has also been associated with a decrease in infectious diseases such as hepatitis A, hepatitis B, as well as hepatitis C and HIV, and is safe during pregnancy. Disadvantages associated with its use include diversion, continued use of illegal drugs, including non-narcotic substances, as well as, addiction to methadone itself [21]. MMT is distinct from utilizing methadone for withdrawal management. A starting dose of 5 mg is often used, increasing the dose as withdrawal symptoms appear. Total doses of 10–20 mg in the first 24 h are common, however, patients with more severe opioid addiction may require initial doses of 30 mg or more. After a stabilizing dose has been achieved, a methadone taper commences, typically decreasing the dose by 20% per day. Methadone has a surprisingly narrow therapeutic window, resulting in deaths due to its respiratory depressant effects and cardiac arrhythmias, even at doses typically used for MMT. As a result, the US FDA issued a safety alert and black box warning in November 2006, followed in 2009 by an expert advisory panel that provided recommendations for therapeutic corrected QT monitoring in methadone treatment [20]. It should be noted, however, that lack of understanding of the long methadone half-life and the time needed to establish stable plasma levels are more likely to be associated with morbidity and mortality than cardiac arrhythmias. Buprenorphine, a semi-synthetic opioid, is a partial agonist at µ-opioid receptors and an antagonist at the k-opioid receptors that shows high affinity for, and slow dissociation from, µ-receptors. It has been used in the effective treatment of opioid dependence since the 1970s and because of its mixed agonist/antagonist properties, has been shown to have a better safety

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special report  Plunkett, Kuehn, Lenart & Wilkinson profile in overdose and a decreased dose-related euphoria when compared with methadone [24–26]. Buprenorphine is associated with less severe and prolonged withdrawal symptoms compared with methadone [27,28]. In addition, its longer elimination half-life allows providers to increase dosage to allow for less frequent administration while avoiding the agonist or withdrawal effects associated with dose escalation in full agonists [29,30]. However, a study by Kosten et al. found that patients treated for 24 weeks had better outcomes with methadone compared with buprenorphine [31]. More recently, a Cochrane review by Mattick et al. found buprenorphine to be statistically significantly superior to placebo medication in retention of patients in treatment at low, medium and high doses. Buprenorphine given in flexible doses was statistically significantly less effective than methadone in retaining patients in treatment (relative risk: 0.80; 95% CI: 0.68–0.95), but no different in suppression of opioid use for those who remained in treatment [32]. A large, randomized, open-label study in healthy patients seeking treatment for opioid dependence stabilized physiologically on a range of buprenorphine doses, could be tapered successfully over 7 days and there is no advantage to prolonging the tapering schedule for weeks [33]. Another large Cochrane review looked at 22 studies involving 1736 patients. Major comparisons of buprenorphine were with methadone, clonidine and lofexidine. Buprenorphine was shown to be more effective in ameliorating the symptoms of withdrawal relative to clonidine or lofexidine. The authors also found that the severity of withdrawal was similar whether managed with buprenorphine or methadone, and that withdrawal symptoms may resolve more quickly with buprenorphine [34]. Marsch et al. reported an attrition rate among opioid-dependent adolescents of 28% after 4 weeks of buprenorphine treatment in a randomized trial comparing buprenorphine with clonidine combined with behavioral therapy [35]. Attrition rates among adults have been as high as 30–45% at 12 weeks, when buprenorphine was continued beyond 12 weeks [36]. Suboxone ® (Reckitt Benckiser Pharma­ ceuticals, Inc., VA, USA) is a combination of buprenorphine and naloxone, allowing for both agonist and antagonist action at the µ-receptor. The goal of this combination is to reduce the risks of diversion and inappropriate use of buprenorphine alone. The oral administration of naloxone is

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inactive, thus the formulation of Suboxone helps prevent diversion in trying to manipulate the buprenorphine component. Naloxone is active in the intravenous formulation and can cause withdrawal. In methadone-maintained patients and in heroin-dependent subjects, intravenous administration of buprenorphine/naloxone combinations precipitated opioid-withdrawal signs and symptoms and was perceived as unpleasant and dysphoric. In morphinestabilized subjects, intravenously administered combinations of buprenorphine/naloxone produced opioid antagonist and withdrawal signs and symptoms that were ratio dependent; the most intense withdrawal signs and symptoms were produced by 2:1 and 4:1 ratios, less intense symptoms by an 8:1 ratio [37]. As such, treatment with Suboxone should begin at the lowest dose possible, and not until 8–24 h after the last opioid use [38]. The practice of using buprenorphine for inpatient opioid detoxification is increasing, although methadone remains the gold standard. A typical buprenorphine detoxification protocol lasts 7–10 days, with once daily dosing. A single dose can minimize withdrawal symptoms for 48–72 h, but some providers prescribe more frequent dosing to ensure therapeutic plasma levels. While protocol varies by institution, day 1 dosage is typically no more than 8 mg, after which the daily dose can approach 8–16 mg of either Suboxone or Subutex (buprenorphine hydrochloride). The dose is then slowly tapered with discontinuation in 36–48 h prior to the intended end of the program [30]. Another intervention with some success in maintenance therapy involves the use of levo-a-acetylmethadol, which is a synthetic opioid that is similar in structure to methadone. Due to its active metabolites, it exhibits a longer duration of action than methadone, capable of suppressing withdrawal symptoms for 48–72 h and thus permitting thrice-weekly dosing [39]. In head-to-head maintenance therapy comparisons, levo-a-acetylmethadol achieved comparable outcomes to methadone, but was withdrawn from the market in the USA in 2003 after ten cases of life-threatening ventricular dysrhythmias were reported in conjunction with its use [40]. Traditional treatment approaches are being challenged by the emergence of innovative techniques based on an understanding of the neurochemistry of addiction. Advocates theorize that by treating the addiction at the neuroreceptor

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Opioid maintenance, weaning & detoxification techniques  level, the detoxification process can be accelerated with treatment time frames that are measured in hours instead of days [21]. These techniques may offer the advantage of eliminating the traditional extreme, subjective withdrawal discomfort that is associated with older techniques and withdrawal symptoms. Ultra-rapid opiate detoxification (UROD) is an example of such a technique [41]. UROD involves placing the patient under general anesthesia and starting a naloxone infusion intravenously. Having the patient under general anesthesia eliminates the subjective complaints associated with withdrawal. The exact duration of UROD varies with institution, but a timeframe of 4–6 h is common. During this period, the patient’s hemodynamics must be closely monitored, as a sympathetic discharge can occur as part of the withdrawal process. Patients may also be given an a-adrenergic agonist, such as clonidine or dexmedetomidine, to provide both analgesia and vascular smooth muscle relaxation. Nonopioid analgesia may also include ketamine, ketorolac and intravenous acetaminophen. Often patients are admitted to the intensive care unit postoperatively so that their symptoms can be managed with adjuncts such as ketamine, dexmedetomidine, clonidine and benzodiazepines [42,43]. The safety and efficacy of UROD is not clear. Despite early enthusiasm for its effectiveness, Kleber noted that there was a lack of strong evidence to support its use [44]. Many initial studies lacked control groups, randomization, and long-term follow-up [41]. Safety concerns, beyond the risk of general anesthesia itself, included pulmonary and cardiac complications, endocrine and renal abnormalities, psychosis, delirium, attempted suicide and death [45–53]. Collins et al. found UROD to be no better than buprenorphine or clonidine in improving withdrawal symptom severity [54]. Finally, UROD has not been shown to offer patients at high risk for relapse long-term benefit or continued resources [55]. Another approach to rapid opioid detoxification involves abrupt discontinuation of opioids followed by initiation of oral naltrexone on the first day. Withdrawal symptoms are managed using nonopioid medications (e.g., clonidine and benzodiazepines), followed by extended-release naltrexone [56]. The goal of this modality is to initiate naltrexone therapy more quickly than gradual agonist tapers. However, as with UROD, many discomforting side effects may result (e.g., vomiting and diarrhea) [34,57].

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a2 agonists, such as clonidine, are often used in conjunction with other agents in the treatment of opioid withdrawal. A Cochrane review found that clonidine does not lessen the intensity of withdrawal, but patients treated with clonidine stayed in treatment longer and had fewer side effects [57]. A major component of withdrawal is anxiety due to high levels of norepinephrine. Clonidine, via negative feedback mechanisms, helps reduce circulating levels of norepinephrine and can thus reduce anxiety [58]. Possible side effects of clonidine include dry mouth, dizziness, constipation and hypotension [59]. Due to this side-effect profile, another agent used in Europe is lofexidine [60]. Lofexidine has comparable clinical efficacy to clonidine, but fewer side effects, particularly postural hypotension. Detoxification with lofexidine can be achieved over periods as short as 5 days [61–63]. Conclusion & future perspective A nonpharmacologic approach to addiction treatment involves the use of acupuncture. Auricular acupuncture, in particular, has been a long-standing therapeutic modality dating back thousands of years. The use of auricular acupuncture has been applied to many conditions including headache, allergic rhinitis, chronic fatigue, anxiety and pain [64–68]. The hypothesized efficacy of auricular acupuncture comes from the idea that the external ear represents a microsystem of the entire body. The ear serves as a miniature homunculus, whereby specific points on the ear correspond to specific areas of the body. Acupuncture’s effect on both emotional responses and neurobiology suggest it may be beneficial for treating conditions with a strong biopsychosocial component, such as addiction [69]. An auricular protocol designed as an augmented treatment for addiction uses 3–5 needles placed in specific points on each outer ear [70,71]. This protocol, known as NADA (National Acupuncture Detoxification Association), has shown some promise in the treatment of both addiction and post-traumatic stress disorder. Part of its efficacy is thought to be due to a calming effect that can be elicited with stimulation of certain auricular points, thus facilitating other psychological and behavioral therapy. Such patient characteristics have been shown to improve participation and retention in addiction treatment programs [72]. Supporters suggest that the NADA principles promote self-efficacy and control, necessary

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special report  Plunkett, Kuehn, Lenart & Wilkinson components for any patient struggling with addiction. Additionally, acupuncture purports to minimize the anxious feelings that sometimes arise as a product of the counseling process and provide positive feelings in the physical, mental and emotional realms that can be guided by the counselor toward wellness [73,74]. However, patient variability due to disparities in educational background, ethnic and cultural differences, as well as varied levels of understanding of the goals of therapy may limit NADA’s effectiveness. There is emerging evidence that genetic variability is a factor in vulnerability to opioid addiction, withdrawal symptoms and effectiveness of treatment. Association studies have linked 67 single nucleotide polymorphisms in eight genes (OPRM1, OPRK1, OPRD1, OPRL1, POMC, PDYN, PENK and PNOC) to opioid addiction phenotypes [75]. Furthermore, genetic variability at the OPRM1 +188 gene position results in epigenetic changes which impede µ‑opioid receptor upregulation in brain tissue of opiate addicts [76]. A murine genetic model identified that 5-HT3 receptor function was required for physical morphine dependence. Translation of this f inding to humans demonstrated that ondansetron pretreatment caused a decrease in withdrawal symptoms [77]. Methadone management of opioid addicts has large interindividual variability, potentially due to genetic factors. A single polymorphism in the dopamine D2 receptor gene has been linked to opiate addiction requiring higher and longer does of methadone for substitution management [78]. Further research in this field has the potential to enable a ‘personalized’ approach to opioid substitution management or maintenance treatment by identifying individuals more susceptible to dependence or withdrawal symptoms. The future direction of both withdrawal management and weaning regimens will have to incorporate a variety of patient populations, including: References 1

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future science group

Opioid maintenance, weaning and detoxification techniques: where we have been, where we are now and what the future holds.

SUMMARY Medically supervised opioid withdrawal is a complex and constantly evolving exercise in multimodal therapy that draws from the expertise of a ...
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