Opioid Effects: Principles & Effects PDF

## 11.5: Principal Effects of Opioids - Depending on the area of the brain or body in which it occurs, opioid-receptor agonism results in both the analgesic and antitussive actions associated with opioid administration as well as major side effects such as nausea and vomiting, sedation, convulsions...

## 11.5: Principal Effects of Opioids - Depending on the area of the brain or body in which it occurs, opioid-receptor agonism results in both the analgesic and antitussive actions associated with opioid administration as well as major side effects such as nausea and vomiting, sedation, convulsions, itching, respiratory depression, endocrine-system suppression, reduced gastrointestinal motility and constipation, urinary retention, and pinpoint pupils (Jamison & Mao, 2015). - More individuals are afflicted by chronic pain than by diabetes, cancer, and heart disease combined, making the administration of opioid drugs a widespread necessity (Jamison & Mao, 2015). - A steady increase in the prescribing of opioids over the past decade has led to a skyrocketing incidence of opioid abuse. - Eighty percent of the opioid drugs prescribed worldwide are dispensed in the United States and, perhaps unsurprisingly, opioid pharmaceuticals have become the most widely abused class of drugs in the United States (Grenald, Largent-Milnes, & Vanderah, 2014; Jamison & Mao, 2015). - Nearly two million Americans meet diagnostic criteria for substance use disorder related to heroin or prescription pain relievers (Center for Behavioral Health Statistics and Quality, 2015). - In primary care and pain clinic settings, the percentage of individuals abusing or misusing opioids is as high as 37% (Chou et al., 2015). - Opioids are amongst the most dangerous of abused drugs. ## 11.5.1: Analgesia - Opioids produce analgesic effects by reducing the excitability of nociceptors, sensory neurons that send information about the physical or chemical injury of tissues along the spinothalamic pathway - from the periphery, to the dorsal horn of the spinal cord, through hindbrain (medulla oblongata and pons) and midbrain (reticular formation and periaqueductal gray) regions to the thalamus, and then on to the somatosensory cortex. - Inhibitory, top-down pathways also exist to control bottom-up pain messages. - These descend from the cortex, travel through the midbrain and hindbrain, and back to the spinal cord. - By binding to m, d, and/or κ receptors in these pain-transmitting and pain-gating regions, opioid drugs reduce the proliferation of action potentials and blunt the pain message. - Morphine, oxycodone, and oxymorphone, for instance, block the transmission of pain primarily by binding to receptors within the thalamus (Olkkola et al., 2013). - Opioid drugs acting within the spinal cord also blunt the transmission of dull, burning pain by binding. ## The sensory component of pain can be broken into several separate types. - We may experience thermoceptive pain (caused by extreme heat or cold), mechanical pain (due to physical damage to muscles, skin, and joints), and visceral nociception (associated with organ damage). - These types of pain can be acute or chronic or may even appear to arise from limbs that have been amputated (phantom limb pain). - μ agonists are effective against a broad range of pain, including all acute types and some chronic types but not phantom pain. - δ agonists are effective against thermal and mechanical pain but are ineffective against visceral pain. - к agonists can be used against visceral pain but are effective only against low-intensity thermal and mechanical pain (Millan, 1986, 1990; Schmauss & Yaksh, 1984). ## Pain is a complicated phenomenon. - Not only does it have a sensory component, but it has emotional aspects as well. - We not only know that a sensation is painful, we also know that we really do not like it. - Opioids also reduce the aversive emotional aspect of pain. - This effect may be mediated through opioid receptors located in various areas of the limbic system, such as the amygdala, as well as in the frontal cortex. ## 11.5.2: Reward - All types of opioid receptors are found within brain circuits associated with reward and implicated in addiction. - Primarily, these are the mesocortical and mesolimbic dopamine pathways that run from the ventral tegmental area (VTA) of the midbrain to the prefrontal cortex, ventral striatum (i.e., the nucleus accumbens; NAcc), and regions of the limbic system, including the hippocampus and amygdala. - The interaction between opioid drug molecules and u receptors residing in the VTA and NAcc is thought to be of utmost importance to the motivational and rewarding effects of opioids. - Dopamine neurons in the VTA are tonically inhibited by the activity of GABAergic interneurons. - The binding of opioid molecules to μ receptors residing on these GABA interneurons attenuates their neurotransmission, thus disinhibiting the activity of VTA dopamine neurons and, consequently, increasing DA release within the NAcc, prefrontal cortex, and limbic system (Nutt, 2014). - This cascade of events mediates not only reward, but also influences the risk for repeated opioid use by enhancing the salience of drug-related contextual cues and incubation of drug craving. - Among the various opioid agonists, those targeting μ receptors possess the highest abuse liability (Devine & Wise, 1994). - The role of 8 receptors in mediating reward and addiction is the subject of some debate (Rodríguez-Arias, Aguilar, Manzanedo, & Miñarro, 2010). - The dense expression of a receptors in cortical and limbic regions suggests their involvement in the biology of addiction, perhaps by driving reward and craving via dopamine-dependent or dopamine-independent processes. - In contrast, activation of к receptors within mesolimbic and mesocortical regions directly inhibits dopamine release. - Drugs of abuse that enhance dopamine levels within brain reward circuits also increase dynorphin levels and, consequently, k-receptor binding. - This suggests that к receptors serve as a feedback mechanism, counteracting drug-induced increases in dopamine to restore homeostasis. ## 11.5.3: Vital Life Functions - In the majority of cases, opioid overdose deaths are due to respiratory depression. - Opioids depress breathing rate and depth mainly through stimulation of µ and 6 receptors located on specific types of respiratory-related neurons within regions of the pons and medulla oblongata (Lalley, 2008). - In addition, the brainstem modulates other vital-life functions and contains control centers for vomiting and coughing. - Their ability to suppress the cough center is why, for centuries, opioids have been used as antitussives. - At one time, most over-the-counter cough medicines contained codeine. - Given its potential for abuse, codeine has been largely replaced by dextromethorphan. ## 11.7: Effects of Opioids on Human Behavior ## 11.7.1: Effects on the Body - When opioids are first administered, two of their most notable effects are nausea and vomiting. - A number of regions in the peripheral and central nervous systems contribute to these effects, including the vagus nerve, gastrointestinal tract, vestibular system, areas of the cortex, and the chemoreceptor trigger zone (CTZ), found within a region of the medulla oblongata called the area postrema (Porreca & Ossipov, 2009). - The blood-brain barrier is incomplete in the CTZ, allowing it to detect impurities in the blood, such as toxins, metabolites, and drugs. - Opioids stimulate nausea and vomiting mainly by binding to µ and 6 receptors within the CTZ. - Together, these regions feed information to an area of the medulla called the vomiting center where the vomiting reflex is either stimulated or repressed. - Tolerance to the nauseating effects of opioids builds quickly and vomiting is usually seen only after the first few administrations of the drug. - With continuing doses, these symptoms dissipate. - The ability of opioids to cause miosis tolerates only slightly with repeated use and therefore narrow pupils are common in opioid users. - Pinpoint pupils are also a symptom of opioid overdose. - Opioids have little direct impact on the heart, though they may slow heart rate and influence function indirectly by stimulating the vagus nerve or the release of histamine (Chen & Ashburn, 2015). - Chronic use of opioids for the treatment of pain does seem to slightly increase one's risk of heart attack (Carman, Su, Cook, Wurzelmann, & McAfee, 2011; Li, Setoguchi, Cabral, & Jick, 2013a). - In addition, opioids lower blood pressure due to dilation of the peripheral blood vessels. - This dilation causes the face and neck to become flushed and warm. - Opioids can also cause profuse sweating which is one of the unpleasant side effects of methadone maintenance therapy. - One of the first medical uses of opium was in the treatment of dysentery and diarrhea, a purpose for which it is still used in severe cases. - Through binding to u receptors along the gastrointestinal tract, opioids impede the functioning of the muscles involved in pushing food through the digestive system. - The decrease in gut motility can lead to intestinal distension (which adds to the nauseating effect of opioids) and cause delay in the emptying of the stomach and intestines (Porreca & Ossipov, 2009; Webster, 2015). - This stops diarrhea but produces constipation instead, which can be a serious medical complication of chronic opioid use. - Opioids that activate k receptors stimulate diuresis (Walsh, Chausmer, et al., 2008) but opioids can also interfere with urination by causing contractions of the bladder sphincter, making it difficult to pass urine. - Opioid use impacts the endocrine system which can lead to impaired sexual function, decreased libido, infertility, and osteoporosis. - Opioids inhibit the secretion of gonadotropin releasing hormone from the hypothalamus, leading to reduced levels of hormones that stimulate the production of testosterone in males and estrogen in females. - Lowered sex-hormone levels are thought to be responsible for males' difficulty in maintaining erection and in reducing sex drive. - One study of men with chronic back pain found that, compared to those who didn't use prescription opioids, those who did were more likely to also have been prescribed medications for erectile dysfunction or testosterone replacement pharmacotherapy (Deyo et al., 2013). - In both males and females, testosterone contributes to sleep quality and energy level, and impacts muscle and bone health (Gudin, Laitman, & Nalamachu, 2015) which may explain why opioid use is associated with increased risk of bone fracture (Li, Setoguchi, Cabral, & Jick, 2013b). - Both male and female opioid users experience diminished fertility. - Heavy use may even cause atrophy of secondary sex characteristics in males and stop menstruation in women. - Historically, opioids were used by women as a means of birth control. - Opioids also impact endocrine function by suppressing activity of the hypothalamic-pituitary-adrenal axis which is considered to be the body's primary long-term "stress system." - Their ability to blunt secretion of stress hormones, such as ACTH and cortisol, may explain some of opioids' relaxing effects (Gudin et al., 2015). - Pregnancies are complicated by direct and indirect effects of opioids and opioid withdrawal. - During pregnancy, the ability of the body to eliminate opioids is increased. - The subsequent reduction in circulating levels of opioids leads to increased demand for the drug, and the probability of withdrawal is greater if the drug supply is irregular. - It is believed that opioid withdrawal during pregnancy can harm the fetus because it causes a decrease in blood oxygen levels. - Numerous other medical complications during the pregnancies of addicted women may arise from harm associated with the addicts' lifestyle. - These complications, which occur in 40 to 50% of pregnant addicts, include anemia, cardiac disease, swelling, liver disease, hypertension, pneumonia, tuberculosis, and infections of the urogenital system, such as bladder infections and venereal disease (Kreek, 1982). - Babies born to addicted mothers have low birth weights and are more likely to be premature and to experience illness and complications after birth. - In general, these problems are less likely in methadone-maintained mothers than in those using street heroin. - One big problem for babies born to dependent mothers is that right after birth, they go through withdrawal because they are no longer exposed to the opioid in the mother's blood. - Withdrawal in neonates is similar to adult withdrawal. - The symptoms include irritability, respiratory distress, yawning, sneezing, tremors, difficulty in sucking and swallowing, and a peculiar high-pitched cry. - Some may even experience seizures. - These symptoms start within 72 hours of birth and may last 6 to 8 weeks (Finnegan, 1982). ## 11.7.2: Effects on Sleep - Despite the fact that morphine is named after the god of dreams, opioids do not cause the user to slip nightly into a deep, restful, dreamy sleep. - They do, however, cause somnolence (drowsiness), lethargy, and nodding throughout the day. - The user may doze off but will soon awaken and will not feel rested. - Sedation is common in long-term opioid users and is associated with poor quality of life (Dhingra, Ahmed, Shin, Scharaga, & Magun, 2015). - These sedating actions are thought to result from direct toxic effects of opioids on neurons, resulting in decreased consciousness, as well as inhibitory influence on acetylcholine activity. - Though individuals experiencing pain are often kept awake by their suffering and prescribed analgesics to help them sleep, long-term opioid use can actually cause insomnia, sleep deprivation, increased muscular tension during sleep, and altered sleep patterns including more time spent in light sleep and a reduction in delta (deep) and REM (rapid eye movement) sleep (Dhingra et al., 2015; Kay, Eisenstein, & Jasinski, 1969). - High rates of sleep apnea and nighttime oxygen desaturation are also common in long-term opioid users. - In this case, not only is there poor quality of sleep but also the potential for opioids to cause death. - Methadone appears particularly dangerous, especially when combined with benzodiazepines (Cheatle & Webster, 2015). ## 11.7.3: Cognitive and Performance Effects - Their capacity to cause sedation and cognitive impairment is the most commonly cited reason why patients discontinue use of prescribed opioids (Dhingra et al., 2015). - Opioid use is associated with inattention, difficulty concentrating, perceptual distortions, memory deficits, executive dysfunction, and psychomotor impairment. - Because pain is also cognitively incapacitating, it is difficult to estimate the degree to which opioid drugs, or the suffering they are intended to relieve, is primarily responsible for these effects. - At its most severe, extreme cognitive dysfunction can result in hallucinations, delirium (confusion, decreased alertness, loss of comprehension), and coma (Dhingra et al., 2015). - Acute administration of opioids to individuals with little or no drug experience produces a greater effect on performance than in those who have previously used opioids (Zacny, 1995). - This is due to a lack of tolerance. - On most types of tasks, opioid-experienced individuals are able to maintain productive work for extended periods even after taking moderate doses of heroin or morphine. - There are numerous cases of individuals who administered opioids in one form or another for years but were still able to pursue successful and even brilliant careers. - One such individual was Dr. William Stewart Halstead, a founder of Johns Hopkins Medical School and one of the most brilliant surgeons of his day. - Halstead pioneered the development of aseptic surgical techniques and the use of cocaine as a local anesthetic and was known as the "father of modern surgery." - Yet, throughout his career, he was addicted to morphine, a fact that he was able to keep secret from all but his closest friends (Brecher & the Editors of Consumer Reports, 1972, p. 35). - Dr. Halstead's success is perhaps even more impressive in light of research indicating that opioid addicts have poor decision-making capacity and behavioral control. - An fMRI study of opioid-dependent individuals performing a go-no go task found that, compared to controls, opioid addicts exhibited an attenuated anterior cingulate cortex error signal when mistakes were made on the task. - The level of anterior cingulate cortex activation that accompanied a false alarm (responding to the wrong target stimulus) accurately predicted task performance, suggesting that a blunted signal could play a role in the loss of control in addiction and other forms of impulsive behavior (Forman et al., 2004). - A study examining the effect of transdermal buprenorphine use on driving ability found no difference in performance capacity (attention, vigilance, reaction time, visual orientation, and motor coordination) between opioid-users and non-users (Dagtekin et al., 2007). - Similarly, an examination of extended-release tapentadol use reported that the majority of participants were deemed fit to drive (Sabatowski, Scharnagel, Gyllensvärd, & Steigerwald, 2014). - In both of these studies, researchers used driving-simulation software to assess performance and participants had been using opioids long-term. - In contrast, a recent population-based study turned to hospital records. - The researchers compared the incidence of road trauma (driving accidents that resulted in an emergency department visit) between individuals who had been prescribed opioids and matched controls who hadn't. - They found a significant relationship between the dose of opioid prescribed and the risk of being involved in a driving-related accident requiring a hospital visitation (Gomes et al., 2013). - These results suggest that opioids do play a role in real-life driving performance, perhaps through mechanisms or aspects of performance not captured in simulated tests or because individuals involved in accidents had lower levels of opioid tolerance. ## 11.7.4: Subjective Effects - Many literary figures were known to be users of opium. - One of the first people to write about the effects was Thomas De Quincey, the English essayist, critic, and writer, author of the now famous Confessions of an English Opium-Eater, first published in 1821. - De Quincey used opium for much of his life and wrote about its effects on his mind and on his life in Confessions. - Like most people in the nineteenth century, he first took opium as a medicine but quickly appreciated its euphoric effects. - After his first dose, his reaction was as follows: > In an hour, O heavens! What a revulsion! What a resurrection from its lowest depths, of the inner spirit!.... > > That my pains had vanished was now a trifle in my eyes; this negative effect was swallowed up in the immensity of those positive effects which had opened before me, in the abyss of divine enjoyment thus suddenly revealed... Here was the secret of happiness, about which philosophers had disputed for so many ages, at once discovered; happiness might now be bought for a penny, and carried in the waistcoat-pocket; portable ecstasies might be had corked up in a pint-bottle and peace of mind might be sent down by the mail.(De Quincey, 1901 pp. 169-170) - De Quincey reported that he had an increased sensitivity in both hearing and vision. - The increase was not so much in the loudness of noises and brightness of lights as in the ability of the mind "to construct out of raw organic sound an elaborate intellectual pleasure" (De Quincey, 1901 p. 179). - And finally, the dreams. - Opioids at higher doses induce a sleepy, trancelike state called a nod, during which the user sees visions or dreams (hence the expression "pipe dreams"). - Unlike the hallucinations from drugs such as LSD, these are more like vivid daydreams: > Whatsoever things capable of being visually represented I did but think of in the darkness... which once traced in faint and visionary colour. They were drawn out by the fierce chemistry of my dreams into insufferable splendor that fretted my heart. (De Quincey, 1901 p. 224) - However, the dreams are not always visual. - Samuel Taylor Coleridge claimed that the words to the famous poem Kubla Khan came to him in a trance after he had taken opium. - Users of opium are firmly convinced that the creative processes are helped by the drug. - De Quincey took opium orally, and though he enjoyed the experience well enough, he missed a subjective effect that is usually experienced only by people who inject morphine or heroin or who smoke opium: the rush. >"This intense momentary feeling of pleasure is experienced when high concentrations of opioid molecules are delivered suddenly to the brain. Rushes are usually described as sexual, rather like an orgasm in the stomach or in the entire body. As one 17-year-old addict described it, "It's just the most intense wonderful feeling.... I worry that I will always be tempted to feel the heroin rush again, because nothing else I've tried comes close to it" (Weil & Rosen, 1983 p. 87). ## 11.7.5: Studies of Mood and Liking - Many authors who write about the subjective effects of opioids stress the euphoric effects and "divine enjoyment" that the drug offers. - Such writings and other accounts have frequently led theorists to speculate that the source of attraction to opioids is relief of anxiety and depression. - But most experiments in which mood and emotional behavior are objectively measured find that positive feelings do not last long and are quickly replaced with emotions that are mostly negative. - In one study conducted at the McLean Hospital in Belmont, Massachusetts, adult male heroin-addicted volunteers were admitted to hospital and kept in a ward for 60 days. - During their entire stay, the ward staff kept track of the men's aggressive and social behaviors and administered standardized psychological tests and mood scales. - After a week of detox, the men were permitted to earn daily heroin injections for a period of 10 consecutive days. - During the first few days of the heroin administration period, heroin relieved tensions and produced euphoria. - However, with continued use and a reestablishment of tolerance to the drug, there was a shift to unpleasant mood states and increased psychiatric symptoms. - Unpleasant feelings were relieved for only a brief period of 30 to 60 minutes after each injection. - In addition to the deterioration in mood, there was a decrease in physical activity and social interaction and an increase in aggressive behavior and social isolation. - These effects diminished during the 7-day methadone maintenance period that followed and during a later 10-day period when the self-administered heroin was blocked by an opioid antagonist (Meyer & Mirin, 1979). - The effects of opioids on mood also differ according to whether the drug is given to experienced users or naïve participants. - In a classic study, Lasagna and his colleagues at Harvard University found that former heroin addicts were more likely to experience positive feelings after morphine administration whereas nonusers reported sedation, mental clouding, and feelings of sickness. - In this experiment, 17 out of 30 former heroin users said that they would like to repeat the experience of morphine a second time, whereas only 2 out of 20 nonusers wanted to repeat (Lasagna, von Felsinger, & Beecher, 1955). - The wide variability in individual responses to initial opioid use might, in part, explain why only a small proportion of patients who receive opioids for short-term pain control progress to developing problems with abuse (Højsted & Sjøgren, 2007). - Studies comparing opioid-addicted and non-dependent users asked to retrospectively assess their initial response to opioids have found a positive correlation between the users' experience of euphoria and degree of drug liking and their later likelihood of abuse or misuse of opioids (de Wit & Phillips, 2012). - The subjective effects of opioids are different when people are in pain. - Conley, Toledano, Apfelbaum, and Zacny (1997) gave morphine to participants who were experiencing the pain of having their arms immersed in icy water. - They found that the pain diminished feelings of being "spaced out," "high," "sleepy," and "light-headed," which were normally caused by morphine in individuals not experiencing pain. - The subjective effects of opioids also differ according to their affinity for various receptor subtypes. - At low doses, pentazocine (which acts as a partial agonist µ and к receptors and a full agonist at d receptors) produces subjective effects similar to those of morphine (i.e., increases in euphoria). - At higher doses, however, people report sedation, dysphoria, feeling "confused," and "having difficulty in concentrating." - These unpleasant effects are reported by nondependent opioid users and, to an even greater extent, nonusers. - Opioids that stimulate the к receptor, such as the partial agonists cyclazocine and pentazocine, can produce quite unpleasant subjective effects including difficulty concentrating, unpleasant bodily sensations, dysphoria, depersonalization, hallucinations, and symptoms of psychosis in both opioid abusers and nonabusers (Zacny, Hill, Black, & Sadeghi, 1998; Zacny & Walker, 1998). ## 11.7.6: Laboratory Studies of Human Self-Administration - Laboratory studies show that opioids produce rewarding (euphoric and drug-liking) effects and act as reinforcers when administered parenterally or intravenously. - The pharmacological profile of an opioid drug, such as its potency, selectivity and affinity for the u receptor, or duration of action, is not, however, a perfect predictor of how much a study participant will like the drug, be willing to work for it, or want to take it again (Wightman, Perrone, Portelli, & Nelson, 2012). - For example, although oxycodone is more potent than morphine which, in turn, is more potent than hydrocodone, the overall magnitude and profile of subjective effects were qualitatively comparable when these drugs were administered intravenously or orally to recreational opioid users (Stoops, Hatton, Lofwall, Nuzzo, & Walsh, 2010; Wilsey, Fishman, Li, Storment, & Albanese, 2009; Zacny, 2003). - Similarly, an abuse-liability comparison conducted in heroin abusers found a disconnect between the rewarding and reinforcing values and the pharmacological profile of intravenously administered opioids. - Subjective ratings of reward magnitude, such as "good drug effect" and "liking" of opioids, were ranked as follows: fentanyl 7 buprenorphine Ú heroin 7 morphine = oxycodone (Comer, Sullivan, Whittington, Vosburg, & Kowalczyk, 2008). - Interestingly, despite its second-place ranking in positive subjective effects, buprenorphine was the only drug for which heroin abusers reported significantly increased ratings of "I feel a bad drug effect" and "I feel nauseated." - Additionally, buprenorphine was the only drug that failed to elicit significant increases in the progressive-ratio breaking point, suggesting that its reinforcing value was no greater than that of a placebo (Comer et al., 2008). - Studies in which oxycodone, hydrocodone, and hydromorphone were administered orally to opioid-nonabusers have likewise reported comparable levels of abuse liability (Walsh, Nuzzo, Lofwall, & Holtman, 2008; Zacny & Gutierrez, 2009). - Another study conducted in opioid-nonabusers found that participants would not self-administer fentanyl unless they were experiencing pain from having their arm immersed in freezing cold water (Zacny & Walker, 1998). - Thus, it appears that the reinforcing capacity of this highly potent opioid depended entirely on its analgesic capacity in non-drug users. - On the whole, the studies outlined above clearly illustrate a disconnect between drug reward and reinforcing values and their pharmacological effects. - Wightman and colleagues (2012) suggest that, along with laboratory data assessing reward and reinforcement values, additional reliable indicators of the abuse liability of various opioid drugs include their price on the street, pharmacy theft rates, ease of acquisition through the medical community or diverted prescriptions, and overdose morbidity and mortality data. - The drug's formulation (especially whether it has temper-resistant properties) and route of administration (e.g., oral vs. parenteral) are also important considerations for abuse liability. - With these factors in mind, oxycodone is near the top of the list in terms of potential for abuse (Wightman et al., 2012). - One consistent finding from the above-discussed research is the association between drug dose and reward. - As long as drug levels are not exceedingly high, there tend to be dose-related increases in positive subjective ratings such as "I feel a good drug effect" and "I like the drug" when opioids are administered intravenously. - Another consistent finding is the association between drug reward, reinforcement, and rate of drug infusion. - As an example, Comer and colleagues (2009) compared the rewarding and reinforcing effects of a 40-mg dose of oxycodone administered intravenously at different infusion rates to heroin-dependent participants. - Participants' ratings of drug liking, good effect, and drug high, and their willingness to work for an additional administration of the dose sampled earlier in the day, corresponded to the drug's delivery speed. - The 40-mg dose of oxycodone was rewarding and reinforcing only when it was administered quickly (over 2 or 15 minutes) rather than slowly (over 30, 60, or 90 minutes; Comer et al., 2009). - Marsch and colleagues (2001) found similar effects related to morphine administration. - Ratings of reward (good drug effect, drug liking, drug high) were greatest when the same dose of morphine was delivered intravenously over a 2-minute period compared to over a 15- or 60-minute period. - Like those cited previously, this study also reported dose-dependent rewarding effects; the higher dose was liked more. - Together, these and other similar studies highlight the important onus on manufacturers to develop slow, extended-release formulations of opioid pharmacotherapies and ones with tamper-resistant properties in order to prevent a rapid, high-dose delivery of opioid molecules to the brain and the potential for abuse that goes with it. - When human laboratory results are compared to those of animal laboratories, a very similar pattern emerges. - In both cases, when the drug is freely available, the amount of self-administered drug is carefully regulated. - The daily dose increases gradually and regularly until it reaches a peak and then remains steady. - There are no intake-abstinence cycles as with alcohol and stimulants, and withdrawal symptoms are not seen. - Figure 11-2 shows data from two similar studies. - In one (presented in the top panel), a human heroin addict self-administered morphine intravenously; in the other (presented in the bottom panel), a rhesus monkey self-administered heroin via the same route (Griffiths et al., 1980). - For the most part, the pattern exhibited by the monkey is similar to that of the opioid addict who attempts to maintain a fairly constant blood level and avoids withdrawal whenever possible. - It is tempting to speculate that the gradual increase in dose over time is a result of tolerance, but this may not be the case. - As you read in Chapter 3 with repeated administrations, the reinforcing effects of many drugs can become sensitized rather than diminished. - The increase in total self-administered dose may be a result of increased reinforcing properties of the drug since it has been shown that, up to a point, larger doses are more reinforcing than smaller doses.