Opioid Dependence PDF

## 11.10: Opioid Dependence Whether repeated exposure to opioids results from an attempt to control chronic pain or from the self-administration of drugs for recreational purposes, the endogenous opioid system undergoes adaptive changes that lead to the development of tolerance and physical depend...

## 11.10: Opioid Dependence Whether repeated exposure to opioids results from an attempt to control chronic pain or from the self-administration of drugs for recreational purposes, the endogenous opioid system undergoes adaptive changes that lead to the development of tolerance and physical dependence, sensitization, and during abstinence, symptoms of withdrawal. ### 11.10.1: Tolerance and Sensitization Repeated opioid use produces rapid and extensive tolerance to most of their effects. Figure 11-2 shows that a human self-administering morphine or a monkey self-administering heroin will, over time, dramatically increase the total daily opioid dose. Within 3 or 4 months of regular use, consumption can increase 10-fold or more. In fact, as mentioned earlier, doses taken by a regular user may be many times higher than that required to kill a nontolerant individual. For a 70 kg, nontolerant individual, a lethal dose of heroin is estimated to be about 50 mg, though a wide range (~12 to 180 mg) has been reported in the literature (Gable, 2004b). In heroin users, the daily administered dose might be as high as 300 mg, without causing death (Lachenmeier & Rehm, 2015). Tolerance to different opioid effects both develops and disappears (during abstinence) at different rates. For example, the constipating effects of opioids never goes away; even with laxative and fiber supplementation, fewer than half of sufferers get relief (Webster, 2015 ☐). The ability of opioids to constrict the pupils only partially disappears with continued use. Conversely, complete tolerance may develop to the analgesic effect of opioids and, paradoxically, pain sensitivity may even be enhanced with chronic use (Yi & Pryzbylkowski, 2015). There are many mechanisms of opioid tolerance. Some involve changes in opioid-metabolizing enzymes, while others are the result of changes in the density or properties of opioid receptors. Earlier, you learned that bound (desensitized) opioid receptors can be physically removed from the cell’s membrane (through a process called endocytosis) to become internalized within the cell (von Zastrow, 2010). Both μ and δ receptors can become internalized only minutes after being stimulated by an agonist. κ receptors are also removed from the cell membrane following agonist binding, but the process is comparatively slow for this receptor subtype (von Zastrow, 2010). The near-immediate reduction in the number of membrane opioid receptors is thought to be a mechanism of acute tolerance (von Zastrow, 2010). Once inside the cell, the bound ligand becomes dislodged and the receptors get sorted: some are degraded, which causes a downregulation of receptor density on the neuron, while others get recycled back to the cell surface, effectively restoring their functionality. Animal research suggests that the correlation between receptor endocytosis and the development of opioid tolerance can be explained by the different outcomes for µ versus d receptors. The cell’s preference for recycling μ receptors promotes a recovery in opioid signaling and a decrease in physiological tolerance. In fact, endocytosis of u receptors may cause them to respond even more strongly to ligand binding following recycling, which could lead to sensitization of some opioid effects. In contrast, internalized d receptors are preferentially degraded rather than recycled, and their loss results in a significant increase in opioid tolerance. Some opioid ligands, including fentanyl and methadone, cause rapid endocytosis of receptors, while others, especially morphine, do so at a much slower rate (von Zastrow, 2010). This varying ability of different opioids to cause molecular changes in the cell is one rationale for opioid rotation (a switch of analgesic medications) in patients with chronic pain (Jamison & Mao, 2015). Because cross-tolerance occurs between opioids, estimating the optimal therapeutic dose when moving from one prescription opioid to another can be extremely challenging and somewhat of a trial-and-error process. A miscalculation in dose can have devastating consequences; physician errors in cross-opioid dose conversions have caused overdose deaths, especially in the case of methadone prescribing (Cheatle, 2015). A lethal human dose of methadone ranges from 20 to 420 mg (Gable, 2004b). Such a wide range reflects the role of physiological tolerance. Cross-tolerance can extend to some drugs, such as alcohol, but not to others, such as stimulants or hallucinogens. Hyperalgesia, or the enhanced sensitivity to painful stimuli, is one manifestation of opioids’ sensitizing effects on neural mechanisms. Individuals receiving methadone maintenance therapy, postoperative patients prescribed opioid analgesics, and laboratory animals with a history of opioid administration all demonstrate or report increased pain sensitivity as a result of opioid-induced sensitization (Lee, Silverman, Hansen, Patel, & Manchikanti, 2011). Intriguingly, acute administration of remifentanil (a short-acting, synthetic m-receptor agonist) to opioid-naïve, healthy human volunteers has been found to produce hyperalgesia within 30 minutes of ceasing drug infusion (Yi & Pryzbylkowski, 2015). Administration of fentanyl, heroin, and morphine have all been shown to increase sensitivity to pain. The neural mechanisms that underlie opioid--induced hyperalgesia are complex. They involve not only spinal dynorphins and the descending pain pathway, but also neurotransmitter systems outside of endogenous opioids, such as glutamate. For instance, prolonged morphine administration produces NMDA-receptor-mediated neurotoxic effects on cells in the dorsal horn of the spinal cord. As the binding of endogenous (or exogenous) opioids blocks the transmission of pain messages through the spinal cord, the death of these cells prevents induction of analgesia (Mao, Sung, Ji, & Lim, 2002 1; Silverman, 2009). ### 11.10.2: Withdrawal Withdrawal from opioids is commonly misunderstood, largely due to inaccurate portrayals in the movies and popular literature. Misconceptions about the severity of heroin withdrawal were formed in the 1920s and 1930s when heroin addicts had easier access to cheaper sources of the drug and took it in much greater quantities than are common now. Few addicts these days are able to take enough drug to cause the severe withdrawal symptoms that are shown in films. Even in its most severe form, however, opioid withdrawal is not as dangerous or terrifying as withdrawal from barbiturates or alcohol. In fact, withdrawal from alcohol can be fatal, but withdrawal from heroin or any other opioid is never fatal on its own. Classic symptoms of withdrawal from heroin proceed in predictable stages. They start 6 to 12 hours after the last administration of the drug, peak at 26 to 72 hours, and, for the most part, disappear within a week. The first signs are restlessness and agitation. Yawning soon appears and may become persistent. The person is able to stay still only briefly and paces about with head and shoulders drooped. The user experiences chills, with an occasional hot flash, and breathes with short, jerky breaths. During this time, goose bumps appear on the skin, resembling that of a plucked turkey (this is the origin of the expression "going cold turkey"). At this point, the addict becomes drowsy and will often fall into a deep sleep known as the yen sleep, which may last 8 to 12 hours. After awakening, the person experiences vomiting, diarrhea, and cramps in the stomach, back, and legs. There may also be twitching of the extremities, which causes the hands to shake, and the legs to kick (this is the origin of the expression "kicking the habit"). There is also profuse sweating; the person’s clothes and bed may become saturated with sweat. These symptoms become progressively less severe and soon disappear altogether. SPECT-imaging reveals widespread reductions in cerebral blood flow to the frontal, parietal, and temporal lobes within the first week of heroin withdrawal. These perfusion deficits are markedly improved after 3 weeks of heroin abstinence (Rose et al., 1996). In laboratory animals, changes in body temperature, teeth chattering, tremor, headshakes, diarrhea, an increase in anxiety-like behaviors, and ultrasonic distress vocalizations are all symptoms of withdrawal (Grenald et al., 2014). The symptoms of withdrawal are similar for all opioid agonists that primarily target the μ receptor, although the discontinuation of less potent opioids, such as codeine or dextropropoxyphene, usually elicits less severe symptoms. Withdrawal symptoms are also milder and craving is less severe following discontinuation of non-selective, partial opioid agonists, such as cyclazocine. Withdrawal can be halted almost instantly, at any stage of the process, by the administration of any m-receptor agonist. This negative reinforcement is a driving factor in relapse to opioid use. Opioid withdrawal symptoms can also be reduced by consumption of alcohol (Ho & Allen, 1981). In a physically dependent individual, withdrawal symptoms can be quickly generated by administering a m-receptor antagonist, such as naloxone. Naloxone-induced withdrawal symptoms are decreased in morphine-dependent, k-receptor knockout mice, suggesting that this receptor subtype plays an important role in withdrawal (Charbogne et al., 2014). The severity of withdrawal depends on the user’s daily dose, but is rarely as drastic as the above description. For most individuals, withdrawal resembles a bad case of the flu. Even though opioid withdrawal is not life threatening, it is extremely uncomfortable and behaviorally disruptive. Recall the study by Thompson and Schuster (1964), described earlier, in which squirrel monkeys were trained to self-administer morphine. An additional component of that study allowed the researchers to measure changes in behavior that occurred in response to a loss of opportunity to self-inject morphine. After the morphine self-administration behavior was acquired, the monkeys were placed on an FR 20 schedule for food reinforcement and a discrete-trials shock-avoidance schedule between periods of morphine availability. Thompson and Schuster found that the behavior of the monkeys on these schedules was not impaired by the self-administered morphine, even though the doses reached relatively high levels. The only time the researchers noticed deterioration in the monkeys’ shock-avoidance or responding for food was when the morphine was no longer available and the monkeys were going through withdrawal. Similarly, the only time Dr. Halstead (the brilliant, morphine-addicted surgeon) experienced any trouble caused by his habit was when attempts to reduce his dosage brought about obvious withdrawal symptoms. ## 11.11: Pharmacotherapies for Opioid Addiction ### 11.11.1: Detoxification One approach to treating opioid addiction is to eliminate the physical dependence by helping the addict get through withdrawal. Historically, when it was widely believed that physical dependence was the cause of addiction, detoxification in and of itself was thought to be an effective treatment for addiction. It is now understood that chronic opioid use causes changes in the brain that last much longer than the overt physical changes precipitated by withdrawal, and that many withdrawal symptoms can be evoked by conditioning mechanisms. Therefore, eliminating the physical dependence does not cure the addiction. There are other long-term treatments that address these problems but they also require abstinence from opioids. Detoxification is therefore necessary before such treatments can be started and is best conceptualized as a transitional state between dependence and abstinence or, at least, harm reduction. There are two approaches to detoxification. In the abrupt approach, withdrawal is initiated suddenly by total abstinence or by the administration of an opioid antagonist, usually naltrexone or naloxone which will displace bound molecules of opioid agonist. The aim is to mitigate the severity and discomfort of withdrawal by getting it over with as quickly as possible. Opioid antagonists shorten the duration of withdrawal, but intensify the symptoms. One way to reduce the aversiveness of withdrawal is to render the patient unconscious or to heavily sedate them by giving general anesthetic. This method can reduce withdrawal to just a few days or even a few hours, but is not recommended because it increases the risk of cardiac and respiratory arrest and death (Diaper, Law, & Melichar, 2014). Another approach to detoxification is to switch from the illicit opioid to a maintenance therapy drug, such as methadone or buprenorphine, and then slowly taper the dose over a period of weeks or, more often, months so that withdrawal symptoms are alleviated. When these first-line pharmacotherapeutics are ineffective, some countries allow for prescription of diamorphine (heroin) as a maintenance drug. Opioids inhibit the release of norepinephrine which, during detoxification, rebounds. Norepinephrine release promotes craving and drug-seeking behaviors (Nutt, 2014). For this reason, as the dose of opioid maintenance drug is systematically reduced, patients may be given a drug such as clonidine or lofexidine, which are a2-adrenergic receptor agonists often used medically to lower blood pressure. a2-adrenergic receptors are located on the presynaptic neuron at noradrenergic synapses and, when activated by an agonist like clonidine or lofexidine, inhibit the release of norepinephrine. This blocks activity in the sympathetic nervous system which is responsible for many of the unpleasant effects of withdrawal, such as sweating. Many other opioid withdrawal symptoms are caused by direct activation of the locus coeruleus, a center in the brainstem that contains the cell bodies of most of the NE neurons in the brain. Clonidine and lofexidine effectively diminish this activity. They also cause sedation, which is helpful during withdrawal. Lofexidine appears to work better than clonidine, and detoxification may be achieved in as little as 5 days (Lobmaier, Gossop, Waal, & Bramness, 2010). Because these drugs have the potential to cause hypotension and bradycardia (slow heart rate), it is safer and highly recommended that withdrawal be medically supervised in an inpatient setting (Diaper et al., 2014). ### 11.11.2: Maintenance Therapies Opioid maintenance therapies are based on the premise that the real harm done by opioids arises from the fact that they are expensive and illegal. It follows that if addicts have a cheap, reliable source of the drug then they will remain healthy and able to pursue careers and lives free of criminal activity. In maintenance therapies, addicts are provided with an opioid agonist, which is made continuously available. Methadone and buprenorphine are considered first-line therapies and, in some countries, diamorphine (heroin) is used as a second-line treatment. #### Methadone Since the early 1920s, it has been illegal for doctors in the United States to prescribe heroin, for any medical reason. Instead, heroin addicts attempting to give up the habit have been given methadone which, as early as 1947, was recognized for its ability to alleviate withdrawal (Bart, 2012). Methadone is the most commonly used pharmacotherapy for opioid addiction and offers several advantages over heroin as a maintenance drug. First, it is more effective when taken orally and, for that reason, is easy, safe, and painless to administer. Second, its long duration of action prevents withdrawal symptoms for 24 hours or more, meaning it can be administered once a day, in clinic, and does not need to be dispensed and brought home by the user. This reduces the risk of misuse or diversion. Third, methadone is a selective, full agonist with high binding affinity at the u receptor. For this reason, it blocks the action of heroin or other m-selective opioid agonists, meaning that, in addition to alleviating symptoms of withdrawal, addicts on methadone will fail to experience the same degree of euphoria and sedation if they relapse to using their opioid of choice. Methadone therapy also reverses the rebound increase in stress-hormone release that occurs during opioid withdrawal (Bart, 2012). Thus, both the negatively and positively reinforcing effects of short-acting opioids are prevented or at least greatly blunted by methadone treatment. At any given time, however, approximately 15% of methadone maintenance therapy patients will be using illicit opioids (Bart, 2012). Substitution of methadone for heroin is not considered a therapeutic end in itself. Methadone is always used in conjunction with psychological or social therapy techniques. In fact, the success of methadone treatment depends heavily on the addict’s having a good, trusting relationship with a well-trained staff (Weddington, 1995). In a typical methadone maintenance clinic, patients are screened to confirm their physiological dependence on heroin or another short-acting opioid. Then, over a period of several weeks, a dosage of methadone (usually 60-120 mg daily) is worked out that will keep patients free of withdrawal symptoms. Unlike with short-acting opioids, once an effective dose of methadone has been established in therapy, it is rare that an increase be required due to tolerance. The lack of progressive physiological tolerance to methadone is not entirely understood but thought to be, in part, related to its NMDA-receptor antagonism (Davis & Inturrisi, 1999). Typically, patients must return to the clinic every day for treatment, prompting some to refer to methadone as "liquid handcuffs" (Bell, 2012). In some programs, compliant patients who demonstrate that they have been free of heroin and associated lifestyle-related harms are permitted to take the drug home and are required to attend the clinic only two or three times a week. Retention rates are high, between 70 and 84% within the first year of treatment (Garcia-Portilla, Bobes-Bascaran, Bascaran, Salz, & Bobes, 2012). Many addicts choose to stay on methadone indefinitely, but with the development of a progressively normalized lifestyle, there are pressures to detoxify altogether. Methadone patients are discriminated against in insurance, licensing, employment, and housing, and the need to attend the clinics regularly interferes with travel and other scheduling commitments. Like any opioid, methadone also produces uncomfortable side effects, including excessive sweating, sexual dysfunction, and constipation. When patients appear ready and motivated to discontinue the drug, doses of methadone are gradually decreased over a period of no less than 6 months so that withdrawal is minimized. Still, detoxification becomes difficult when the dosage gets low. Should a patient decide to abruptly stop taking methadone after chronic treatment, there is less craving and a milder, albeit longer, withdrawal period compared to that of morphine. As a maintenance drug, methadone offers the benefit of reduced sickness and death associated with illicit drug use (Sporer, 2003), improved functioning and quality of life, normalization of immune and endocrine functions, and reduction in criminality, risk behaviors, and the transmission of infectious diseases including HIV/AIDS (Garcia-Portilla et al., 2012; Ling, Rawson, & Compton, 1994; Veilleux, Colvin, Anderson, York, & Heinz, 2010). #### Buprenorphine Like methadone, buprenorphine is considered a first-line treatment for opioid addiction. It is most often taken as a sublingual tablet or administered transdermally through a patch. It has certain advantages over methadone, including a slower dissociation from the μ receptor and, consequently, a longer half-life which allows for less frequent dosing. As levels build in the body, it may be administered every second day, rather than daily like methadone, which makes it a more convenient and less expensive form of treatment. Buprenorphine also causes less sedation and less dysphoria compared to methadone. This is because it acts as a partial, rather than full, agonist at μ receptors and because it fully antagonizes d and k receptors. Additionally, its submaximal stimulation of u receptors means less risk of respiratory depression and overdose death, but also a ceiling effect in its ability to reduce craving and symptoms of withdrawal. Compared to methadone-maintained patients, those taking buprenorphine experience more withdrawal symptoms and less positive reinforcement from their medication. The fact that buprenorphine’s effects plateau at about 16 mg per day is beneficial in preventing abuse (because self-administering a higher dose fails to yield euphoria), but also translates into fewer patients remaining in treatment or a greater "revolving door" effect where patients cycle frequently in and out of treatment (Bell, 2012). Despite being a partial agonist, buprenorphine has a high affinity for u receptors and, like methadone, competitively displaces short-acting opioids, such as heroin, from receptors. Buprenorphine is also similar to methadone in its ability to suppress stress-responsive hormones whose levels become elevated during withdrawal (Bart, 2012). Withdrawal from buprenorphine is less severe than that from methadone, which might be a contributing factor to higher noncompliance rates (Mattick, Breen, Kimber, & Davoli, 2014). Patients maintained on buprenorphine have greater autonomy and flexibility in that the drug is prescribed for home self-administration as opposed to dispensed daily in a clinic. A real concern, of course, is that of drug diversion and misuse. To mitigate abuse potential, buprenorphine can be combined with naloxone in tablets that usually contain a 4:1 ratio. If the tablets are taken as instructed, the naloxone (which has poor bioavailability when taken orally or buccally) is not absorbed into systemic circulation whereas the buprenorphine is. However, if the tablets are crushed and injected or snorted for a more intense effect, the bioavailability of naloxone is high; it will be absorbed and will block the effect of the buprenorphine. #### Heroin For residents of Switzerland, the Netherlands, the United Kingdom, Germany, Spain, Denmark, Belgium, Canada, and (soon) Luxembourg, diamorphine (heroin) pharmacotherapy is available as a second-line treatment for those who do not respond well to methadone or buprenorphine. Heroin-assisted treatment (HAT) has the obvious advantage of providing a safe source of the drug to heroin addicts, but there are obvious disadvantages as well. Whereas injectable or inhalable heroin is highly effective in alleviating craving and symptoms of withdrawal, its short half-life means it must be administered 2 to 3 times daily. With the extremely high risk of abuse or diversion, availability is strictly controlled and the drug is administered only in a clinic. This entails even more frequent visits to a clinic than are required of methadone patients. Yet, a recent meta-analysis of randomized controlled trials assessing HAT found significantly greater reductions in the use of illicit heroin as compared to methadone patients (Strang et al., 2015). Other studies have reported similar findings (Ferri, Davoli, & Perucci, 2011; Oviedo-Joekes et al., 2010; Strang et al., 2010) which may be attributable to the significantly greater reduction and severity of cravings (Blanken, Hendriks, Koeter, van Ree, & van den Brink, 2012). In addition, HAT reduces addicts’ use of alcohol and other drugs (Blanken, Hendriks, van Ree, & van den Brink, 2010; Eiroa-Orosa et al., 2010; Haasen et al., 2009). Use of heroin as a maintenance drug is associated with a decrease in mortality rates (Garcia-Portilla et al., 2012), reductions in crime (Killias, Aebi, Pina, Egli, & Skovbo Christensen, 2009; Löbmann & Verthein, 2009; Frick et al., 2010), a destabilization of local illicit drug markets and decreased demand for illegally sourced heroin (Killias & Aebi, 2000; Robelo, 2013) and, although HAT-related costs are initially greater than those associated with methadone treatment, these are more than offset by savings in criminal justice and health care (Dijkgraaf et al., 2005). HAT is associated with improvements in users’ physical and mental health, employability, social relationships, and quality of life (Karow et al., 2010; Nosyk et al., 2011; Schechter & Kendall, 2011; Verthein, Haasen, & Reimer, 2011). It is for these reasons that harm-reduction advocates in the United States want zero-tolerance laws on heroin amended to allow HAT pilot projects in the United States (Drug Policy Alliance, August 2015). ### 11.11.3: Antagonist Therapies Maintenance therapies were originally developed at a time when it was widely believed that fear of withdrawal was the primary motivation for taking opioids. We now understand that being physically dependent is not the crucial factor in addiction, rather it is the reinforcing effects of the drug that motivate its use and, in the case of treatment, relapse. The primary benefit of maintenance therapies is that they are a legal, cheap, and reliable form of positive reinforcement that substitutes for an expensive and illegal one that requires an unhealthy, risky lifestyle. For many people, however, maintenance is not enough—they want to be opioid free. For this reason, antagonist therapies were developed as an abstinence-focused intervention. In antagonist therapies, patients are first detoxified from the opioid drug to which they are addicted, by using one of the methods described earlier, and kept abstinent for 7 to 10 days. This stage of the process can be very difficult, and the dropout rate is extremely high; fewer than 20% of patients remain in treatment for 6 months (Bart, 2012). This is followed by the relapse-prevention phase. As early as possible, addicts are given daily doses of the antagonist, naltrexone, when they come for therapy. This is usually at an outpatient day program where they also have educational seminars, recreational activities, and group therapy. Naltrexone is a pure antagonist, like naloxone, but has a longer half-life of about 9 hours. It can be taken orally, is extremely safe, and has no abuse potential. The ability of oral naltrexone to reduce craving does not seem to be any greater than that of a placebo (Dijkstra, De Jong, Bluschke, Krabbe, & van der Staak, 2007) and naltrexone does not help rebalance stress-hormone systems dysregulated by withdrawal (Shaham et al., 1997). But the most important property of naltrexone is that it completely blocks all of the effects of opioids including the euphoric and reinforcing effects. Within 24 to 48 hours following administration of oral naltrexone, or for the 3 to 4 weeks following i.m. injection of an extended-release formulation, injection or inhalation of even large doses of heroin cause the user to feel nothing. In theory, this should discourage opioid use and even cause the opioid-seeking response to extinguish. Even though early results were encouraging (Kleber, 1974) and patients receiving extended-release naltrexone injections do report fewer days of illicit opioid use (Bart, 2012), an unexpected difficulty has arisen with antagonist therapies. When drug users know that they have taken an antagonist, they seldom try to shoot heroin because they know that it will not have an effect. When they start taking the antagonist, they usually stop using heroin so suddenly that the positive reinforcing effects of the heroin on heroin-seeking behavior never get a chance to extinguish. It seems that taking the naltrexone becomes a discriminative stimulus, signaling that the reinforcing effect is not available. When they want to take heroin, they simply stop taking the naltrexone. For this reason, antagonist therapies have high noncompliance and dropout rates. Compliance problems can be partially addressed by using alternative administrations of naltrexone, such as long-lasting, sustained-release depot injections and naltrexone implants. Studies have shown that these extended release naltrexone administrations lengthened treatment and seemed to lower heroin craving (Comer et al., 2006). Success rates with antagonist therapies are much higher in people who are extremely motivated to quit, have strong family support, have legitimate professional careers to pursue, or who have been ordered by a court to discontinue heroin use (Jaffe, 1987; Veilleux et al., 2010).