The Use of Oxycodone and Morphine - Research Paper Example

? Effective and Non-effective Medications Used to Treat OxyContin and Opioid Addiction OxyContin is an opioid drug approved by the FDA for pain management and has been discovered to be highly addictive. New drugs are needed to deter withdrawal symptoms for people being treated for OxyContin addiction. This article discusses novel drugs developed for OxyContin and opioid addiction treatment which are both effective and non-effective. Recent developments in the neuroscience of opioid addiction are also discussed. These advances may offer new treatments for blocking effects of opioid withdrawal. Effective and Non-effective Medications Used to Treat OxyContin and Opioid Addiction OxyContin is an extended release form of oxycodone, which was approved by the Food and Drug Administration in 1995 for the treatment of chronic pain. The FDA approval of this drug has played a role in overdose and death, as well as addiction, in the recent past (Okie, 2010). The molecular structure of OxyContin is similar to that of morphine, and is a member of the Phenanthrene family of compounds. OxyContin, or oxycodone, is a schedule II drug according to the Drug Enforcement Agency, and is used to treat moderate to severe pain and is DEA listed as a highly addictive medication. The drug itself, and not the metabolites, is the main cause of analgesia (Trescot et Al., 2008). Oxycodone and morphine were compared for similar psychotropic effects and dosage in healthy humans. It was found that the dosage ratio of oxycodone and morphine was approximately 3:1, as had been established in previous studies, but that the subjects experienced more pronounced psychotropic effects with oxycodone. The relief of pain, however, was similar with both drugs. Psychomotor impairment was similar with both drugs as well (Zacny and Lichtor, 2007). Intravenous administration of oxycodone, hydrocodone, and morphine was studied in healthy individuals to determine effects and potency. It was discovered that all three drugs had similar effects inducing dysphoria. However, potency was determined to be greatest in oxycodone, then morphine, then hydrocodone (Stoops et Al., 2010). The effects of oxycodone were compared to those of lorazepam and morphine in healthy individuals. Psychotropic effects were more pronounced in oxycodone treated patients compared to those treated with lorazepam. Unpleasant effects as determined by the patients were greater in oxycodone treated patients compared to those of lorazepam (Zachney and Gutierrez, 2002). Opioid withdrawal suppression was examined in healthy individuals with tramadol. After a regimen of oxycodone higher doses of tramadol suppressed withdrawal effects, as studies indicated. Feelings of sickness and nausea were initially associated with these effects, followed by suppression of oxycodone withdrawal effects. It was suggested that tramadol may be an effective drug for treating oxycodone withdrawal effects in humans (Lofwall et Al. 2007). Tramadol has low rates of diversion and abuse and mixed pharmacologic actions, including modest opioid agonist activity, and is an unscheduled atypical analgesic. To characterize the opioid withdrawal suppression efficacy of oral tramadol was the purpose of the study. Opioid dependent, residential adults were maintained on morphine for approximately six weeks. Substituting placebo for scheduled morphine doses 17.5 hours before experimental sessions that occurred twice weekly was the method for producing spontaneous opioid withdrawal. Under double-blind, double- dummy, randomized conditions, the acute effects of placebo, tramadol, naloxone, and morphine were tested. Outcomes included physiologic indices, psychomotor/cognitive task performance, and observer- and subject-rated measures. Prototypic opioid antagonist and agonist effects were produced by naloxone and morphine, respectively. Effects most similar to placebo were produced by Tramadol 50 and 100 mg. Tramadol 200 and 400 mg initially produced significant dose-related increases in ratings of “bad effects” and “feel sick,” followed by evidence of opioid withdrawal suppression. Tramadol did not produce any clinically significant physiologic changes nor significant increases on measures of positive drug effects. Tramadol, at doses of 200 and 400 mg, without significant observer- and subject-rated opioid agonist effects, demonstrated evidence of opioid withdrawal suppression. High risk for tramadol abuse in opioid dependent individuals was not suggested by the profile of action. Therefore, tramadol may be a useful medication for treating opioid withdrawal (Lofwall et Al., 2007). Female rats were used to study the co-administration of ultra-low doses of naltrexone with oxycodone. It was demonstrated that ultra low dose, but not middle dose or high dose, of naltrexone was effective in blocking withdrawal effects of oxycodone, as well as blocking “reward effects” of the opioid. It was suggested that naltrexone may be an effective drug for blocking addiction of oxycodone (Olmstead and Burns, 2005). Opiate analgesia and attenuated tolerance and withdrawal are enhanced by ultra-low-dose opioid antagonists. The objective was to determine whether ultra-low dose naltrexone co-administration alters the aversive effects of opiate withdrawal or the rewarding effects of opiates. The conditioned place preference and conditioned place aversion paradigms were used by the authors to assess whether ultra-low-dose naltrexone alters the aversive aspect of withdrawal from oxycodone or morphine or the acute rewarding effects of either drug. A range of naltrexone was tested in the oxycodone conditioned place preference experiment to assess the dose response for ultra-low-dose naltrexone. The authors used single conditioning sessions and female rats, as females are more sensitive to the conditioning effects of these drugs, in order to avoid tolerance or sensitization effects. The conditioned place preference to morphine and the conditioned place aversion to withdrawal from chronic morphine was blocked by ultra-low-dose naltrexone. The conditioned place aversion to withdrawal from chronic oxycodone administration was also blocked by co-administration of ultra-low-dose naltrexone. A biphasic dose response was revealed by the effects of naltrexone on the conditioned place preference to oxycodone. Oxycodone combined with the highest dose produced a trend toward a conditioned place preference, the two lowest doses blocked the conditioned place preference, and the middle dose was ineffective. Ultra-low-dose naltrexone co-administration blocks the anhedonia of withdrawal from chronic administration of oxycodone or morphine, as well as the acute rewarding effects of analgesic doses (Olmstead and Burns, 2005). However, there was no effect of low dose administration of naltrexone on oxycodone addiction, as determined by a study utilizing the addition of low dose of naltrexone with oxycodone in human opioid abusers (Tompkins et Al., 2010). Clinicians have increased opioid prescribing for alleviation of both acute and chronic pain and, consequently, prescription opioid abuse has risen dramatically in the United States. Decreased risk for abuse of opioid analgesics is needed. Opioids combined with ultra-low-dose naltrexone may have increased analgesic potency and have suggested reduced abuse or dependence liability as determined by preclinical and clinical studies. Addition of ultra-low-dose naltrexone may decrease the abuse liability of oxycodone in humans and was the focus of this study. The subjective and physiologically effects of combining oral oxycodone and ultra-low naltrexone doses in 14 experienced opioid abusers was examined in this double-blind, placebo-controlled study. Comparison in a within-subject crossover design consisted of the following: placebo, oxycodone 20 mg, oxycodone 40 mg, plus each of the active oxycodone doses combined with 0.0001 and 0.001 mg naltrexone in seven acute drug conditions given at least 5 days apart. Abuse liability indices showed the methods were sensitive to detecting opioid effects. Oxycodone conditions and placebo as well as between 20 and 40 mg oxycodone doses on positive subjective ratings on observer- and participant- rated opioid agonist effects, and on a drug-versus-money value rating, consisted of significant differences between all. Addition of either naltrexone dose on any abuse liability indices showed there were no significant differences or evident trends. In experienced opioid abusers, the addition of ultra-low dose naltrexone did not decrease abuse liability of acutely administered oxycodone (Tompkins et Al., 2009). In response to naloxone precipitated withdrawal of opioid drugs, lofexidine and clonidine were examined in healthy opioid-dependent humans. In response to the withdrawal, indicators such as heart rate and pupil dilation were studied. It was determined that other drugs needed to be administered for effective response to withdrawal, although lofexidine and clonidine helped in withdrawal suppression of opioids (Walsh et Al., 2003). To determine the effect of injection depot formulation to withdrawal from and resistance to exogenous challenge of opioids, bupenforene was examined in healthy human patients with opioid dependence. Bupenforene had positive effects in regard to withdrawal symptoms, as well as blocking the effects of additional opioid challenge compared to placebo. As a possible treatment for opioid withdrawal and challenge, it was suggested that bupenforene be further studied (Signon et Al., 2004). In “Chronic and intermittent morphine treatment differently regulates opioid and dopamine systems: a role in locomotor sensitization,” different behavioral adaptations that could be explained in part by distinct changes occurring in dopamine and opioid systems could be induced by chronic and intermittent morphine treatments (Le Marec et Al., 2011). In “induction of opioid-dependent individuals onto buprenorphine and buprenorphine/naloxone soluble-films,” safe and effective delivery methods for opioid induction support the use of B and B/N soluble films (Strain et Al, 2011). In “Slow-release oral morphine for opioid maintenance treatment: a systematic review,” slow-release oral morphine is an effective alternative to methadone opioid maintenance treatment (Jegu et Al., 2011). In “Buprenorphine and opioid antagonism, tolerance, and naltrexone-precipitated withdrawal,” effects of buprenorphine are augmented during chronic treatment by the ?-antagonist, but not the ?-antagonist and in addition, the daily administration of 0.3 mg/kg buprenorphine is adequate to produce opioid dependence, suggested by the leftward shift of the naltrexone dose-effect function.(Paronis and Bergman, 2011). In “Constitutively active ?-opioid receptors,” the potential to fine-tune opioid pharmacotherapy may be offered by a better understanding of constitutive activity at the ?-opioid receptor and provide information useful in developing ligands that access subsets of receptor conformations (Connor and Traynor, 2010). In “Agmatine modulates neuroadaptations of glutamate transmission in the nucleus accumbens of repeated morphine-treated rats,” modulating extracellular glutamate concentration and NMDA receptor expression demonstrated that agmatine could modulate the neuroadaptations of glutamate transmission in the nucleus accumbens in the case of morphine dependence (Wang et Al., 2011). In “Buprenorphine implants for treatment of opioid dependence: a randomized controlled trial,” the use of buprenorphine implants compared with placebo resulted in less opioid use over 16 weeks, as assessed by urine samples among persons with opioid dependence ( Ling et Al., 2010). In “Effect of ultra-rapid opiate detoxification on withdrawal syndrome,” ultra-rapid opiate detoxification (UROD) undergone by patients with opioid dependency who underwent UROD showed the highest rate of withdrawal symptoms at one hour after anesthesia, and most of these symptoms subsided after 24 hours. It was concluded that UROD can be safely applied for detoxification of patients with opioid dependency (Safari et Al., 2010). In “Sustained release d-amphetamine reduces cocaine but not 'speedball'-seeking in buprenorphine-maintained volunteers: a test of dual-agonist pharmacotherapy for cocaine/heroin polydrug abusers,” oral sustained release d-amphetamine (SR-AMP) can attenuate intranasal cocaine and intramuscular hydromorphone self-administration, as well as selectivity, in cocaine/heroin polydrug abusers (Greenwald et Al., 2010). In “Essential role of the cAMP-cAMP response-element binding protein pathway in opiate-induced homeostatic adaptations of locus coeruleus neurons,” it was discovered that prolonged exposure to morphine induces homeostatic plasticity intrinsic to locus coeruleus (LC) neurons, and involves up-regulation of the cAMP-CREB signaling pathway, which then enhances LC neuronal excitability (Cao et Al., 2010). In “Episodic withdrawal promotes psychomotor sensitization to morphine,” contribution to the development of addiction was discovered by effects of intermittent drug exposure, and that episodic withdrawal may also have a pervasive role (Rothwell et Al, 2010). In “The role of beta-arrestin2 in the severity of antinociceptive tolerance and physical dependence induced by different opioid pain therapeutics,” opioid-mediated responses in vivo in a ?arrestin2-dependent manner lend further evidence that distinct agonists can have a differential impact (Raehal and Bohn, 2011). In “Trait-like impulsivity does not predict escalation of heroin self-administration in the rat,” high impulsivity on 5-choice serial reaction time test has been shown to predict loss of control over cocaine intake, but that this does not generalize to a loss of control over heroin self-administration. Trait-like impulsivity plays a role in stimulant but not opiate addiction, and there is an important distinction in vulnerability mechanisms underlying cocaine and heroin addiction (McNamara et Al., 2010). In “Reinforcer-dependent enhancement of operant responding in opioid-withdrawn rats,” enhanced operant, while selective, is generalized to some nonopioid reinforcers, as observed under opioid-dependent and withdrawn conditions (Cooper et Al., 2010). To elucidate their mechanism of action and addictive potential in vulnerable humans, benzodiazepines were studied. Through molecular modification of the drug, it was determined that addictive potential of benzodiazepines could be deterred (Tan et Al., 2010). The neural circuitry in benzodiazepine addiction in humans was also determined, and it was suggested that knowledge of this circuitry could be utilized to deter addiction (Riegel and Kalivas, 2010). In “Controversies in translational research: drug self-administration,” it was discussed that the utility of animal and human models in predicting clinically useful medications is variable. To evaluate potential pharmacotherapies for drug abuse, laboratory animal and human models of drug administration were tested. To compare results to clinical outcomes, the objective of the study was to track how antagonist, agonist, and partial agonist medication approaches influence heroin and cocaine self-administration by rodents, non-human primates, and humans. The demonstrated clinical utility across species was demonstrated by all three medication approaches, as heroin self-admistration was decreased. It is important to assess a medication’s abuse liability preclinically to predict medication abuse and compliance, and of considering subject characteristics when interpreting medication effects, as demonstrated by the heroin data. The effects of ecopipan, modafinil, and aripiprazole were consistent in the clinic and laboratory, provided that the medications were administred repeatedly before self-administration sessions, as demonstrated by the data collected for cocaine. In the human laboratory, modafinil attenuated cocaine’s reinforcing effects and improved treatment outcome, while ecopipam and aripiprazole do not appear promising in the clinic, as these drugs increased the reinforcing effects of cocaine. Recent data with modafinil suggest that the human laboratory model identifies medications to treat cocaine dependence, as the self-administration model has reliably identified medications to treat opioid dependence. When subjective effects are the primary outcome measure, but not when self-administration is the outcome, there have been numerous false positives. Medication maintenance and the concurrent assessment of a range of behaviors are factors relevant to the predictive validity of self-administration procedures to determine abuse liability and specificity of effect (Haney and Spealman, 2006). In “Enhancement of cocaine’s abuse liability in methadone maintenance patients,” the pharmacodynamics effects of single doses of cocaine were examined to determine whether methadone maintenance alters effects. While living on a research unit, twenty-two current users of IV cocaine who were not seeking treatment for their illicit cocaine use participated. As a treatment for their opioid abuse, eleven were maintained on methadone 50 mg PO daily. Also, opioid-free urines throughout the study were provided by 11 who were opioid abusers but not physically dependent on opioids. In random order under double-blind conditions in separate test sessions, each subject received acute cocaine challenge doses of 0, 12.5, 25, and 50 mg intravenously. Before injection and for 2 hours after, physiologic and subject-rated responses were measured. Cocaine challenge sessions occurred 15.5 hours after the daily methadone dose in the methadone maintenance group. In the methadone-dependent and nondependent groups, there were significant differences. In response to cocaine administration, cocaine-induced increases in subject ratings of drug effect, rush, good effects, liking, and desire for cocaine and in heart rate and baseline differences related to chronic methadone administration. Not associated with cocaine administration were lower respiration rates and pupil diameter, and higher skin temperature. These results suggest a pharmacological basis for the high rates of cocaine abuse among methadone maintenance patients, indicating that the positive subjective effects and some physiological effects of cocaine are enhanced in methadone-maintained individuals (Preston et Al., 1995). Oral Delta-9-tetrahydrocannabinol (Delta(9)-THC; Marinol) is medically available for the treatment of wasting syndromes related to HIV/AIDS and nausea associated with cancer chemotherapy. Its reinforcing effects remain largely unknown. To characterize the reinforcing effects of oral Delta(9)-THC in experienced marijuana smokers, this study was conducted under controlled laboratory conditions. This 17-day residential study was completed by ten healthy male marijuana users. Participants received a 2 US dollars voucher (redeemable for cash at study's end), a "sample" oral dose of Delta(9)-THC (0, 10, 20 mg), and an alternative reinforcer on days 2, 6, 10, and 14, at 0900 h. Over the next 3 days, they had 11 opportunities to receive a 2 US dollars voucher or to self-administer the sampled dose of Delta(9)-THC. More often than placebo ( Read More