Opiate Receptor Blockers in Clinical Practice

History of opiate receptor blockers originates from the middle of the XX century, when the first allyl derivatives of opium derivatives [1-3] were synthesized . The experimental tests of obtained compounds revealed that substitution of a methyl group at the nitrogen atom of a morphine nucleus (Fig. 1) by more massive hydrocarbon radicals is accompanied by a significant increase in affinity of such modified molecule to the opiate receptors of the brain [4-6].

opiate receptor blockers

Fig. 1. Substitution of a methyl group (-CH3) at the nitrogen atom of a morphine nucleus of opioids by hydrocarbon radicals (-R3). It is known that for providing the normal transmission of nerve impulses across the synapse it is necessary that the ligand molecules (substances that can interact with appropriate receptors, in this case – opioids) after interaction with receptors of the postsynaptic membrane must be removed quickly from the synaptic gap or enzymatically destroyed inside it in order to make room for the next portion of the ligands. The increased affinity of modified mentioned opioids led to the fact that they stayed longer than usually on opiate receptors, were slower removed from the synaptic gap and, therefore, violated the transmission of nerve impulses in the synapses of endogenous opioid systems that are relevant to the management of the perception of pain stimuli and to the formation of emotions. Thus, the synthesized compounds appeared opium antagonist properties. In the process of chemical transformation of “pure” opium agonists (drugs/or narcotics) were produced substances with intermediate properties, so called. agonist-antagonists, as well as “pure” opium antagonists that should be considered a classical example of transformation from quantity (affinity to receptors) to quality (agonism-antagonism, Fig. 2). In this case, only “pure” opioid antagonists, namely, naloxone and naltrexone can be rightfully called the blockers of opiate receptors.

opiate receptors - from agonistic to antagonistic

Fig. 2. The process of changing the properties of opioids (from agonistic to antagonistic) with increasing their affinity to opiate receptors. For half a century of clinical application of opiate receptor blockers the global medical community has passed all stages of evolution of the well-known views on any newly found phenomenon : “enthusiasm → disappointment → rightful place in everyday practice”. The most vivid picture of this evolution can be seen by the dynamics of the number of publications devoted to the opiate receptor blockers in the medical journals (Fig. 3), according to the information system of the National Library of Medicine of the United States of America «MedLine» [7].


Fig. 3. Dynamics of the number of publications containing the words either «naloxone» or «naltrexone» according to the results of search information system MedLine [7]


It is clearly seen that the peak of interest was paid to naloxone in the 80-ies of XX century. while the number of publications devoted to the study of naltrexone has been increasing continuously over the past thirty-five years since its synthesis up to the present time. Areas of clinical application of naloxone and naltrexone are determined by the peculiarities of their pharmacokinetics. Naloxone – a short-acting drug. Its half-life is measured in tens of minutes. Because of the intense biotransformation in the liver Naloxone is ineffective when taken orally, so it is assigned exclusively for parenteral use (intramuscularly or intravenously). In contrast to naloxone, naltrexone is effective when taken orally. With this method of administering its effect occurs within 1-2 hours and lasts up to 24-48 hours. Such long-term effect after oral administration can be explained by the fact that the main metabolite of naltrexone – 6-beta-naltreksol – also has the properties of opiate receptor blocker, and the period of its half-life (approximately 13 hours) is about 3 times longer than the half-life of the naltrexone (approximately 4 hours). In view of these circumstances, naloxone is mainly used for treating acute poisoning by opioids, and naltrexone is an integrated part in a complex treatment of opioid dependence. However, this division of “spheres of influence”, as it will be shown later, is very conventional. Naloxone in the diagnosis and treatment of opioid dependence. Management of acute opioid poisoning is not the only area of naloxone application . For example, naloxone is used to determine the presence and severity of dependence on opioids [8]. Because of possible painful for the patient’s manifestations of withdrawal syndrome naloxone used for this indication, mainly in the case of an unconscious patient. In this case, diagnostic purposes (determination of the kind of psychoactive substance that caused the coma) and therapeutic purposes (emergency) use of this drug can be achieved simultaneously. Additionally, naltrexone challenge test is usually carried out before enroll for the long-term of anti-relapse treatment by naltrexone. Naloxone at a dose of 0,2-0,4 mg is being given intravenously for 5 minutes, subcutaneously or intramuscularly, and then the patient must be carefully observed, trying to detect early signs of withdrawal syndrome: dilated pupils, tachypnea, lacrimation, rhinorrhea and sweating. If for the first 15-30 minutes, there is no reaction to the introduction of naloxone, then naltrexone is administered intravenously in repeated doses of 0.4 mg or subcutaneously at a dose of 0,4-0,8 mg and again the patient is being observed . Negative re-introducing reaction to naloxone indicates the absence of physical dependence on opioids at the time of the test. It should be remembered that naloxone test may be negative for the patients who suffer opiate addiction if they are in a state of remission.


Conventional (oral) forms of naltrexone in clinical practice. Naltrexone – one of the few drugs that was originally created for the treatment of opioid addiction. Naltrexone has a high affinity for μ-opioid receptors. It is ingested orally and has no psychoactive properties, which means that naltrexone cant be abused. Treatment of opioid dependence with naltrexone begins immediately after the completion of detoxification and the negative challenge test with naloxone (see above) in doses of 50 mg – for daily oral administration of 100 mg – for ingestion in a day or 150 mg – Oral 2 days [9-11]. Naltrexone is well tolerated by patients. Many studies point its ability to provide a moderate stimulating effect on patients who are dependent on opioids, favorably affect kind of asthenic and anorexic disorders. [12, 13]. However, some patients in a period of adaptation to naltrexone experience increased level of anxiety and irritability. The emergence of dysphoric reactions upon repeated administration of naloxone is considered as a marker of incomplete treatment of withdrawal [14].

Naltrexone side effects

The frequency of other side effects (nausea, abdominal pain and headaches) is relatively small. The most serious side effect of naltrexone is hepatotoxic effect, which is noted only in case of using very high doses of naltrexone (1400-2100 mg / week). It should be noted that naltrexone was officially approved for use in USA as a treatment for opiate addiction on the basis of its pharmacological properties. The main problem limiting the effectiveness of naltrexone is a low compliance and high rate of relapse after cessation of naltrexone therapy [15]. Using a special reward for taking naltrexone [16, 17], use of naltrexone in combination with psychotherapy and counseling [18], family therapy [19], as well as use of a possibility to control the patient’s behavior by law enforcement (parolees) [19, 20] significantly increase compliance and efficiency of naltrexone therapy. However, the role of naltrexone in treatment of addictions is not limited to opiate addiction. Despite the fact that alcohol, unlike opioids, doesn’t interact with the opiate receptors, the use of naltrexone in clinical case of alcohol dependence is pathogenetically substantiated. Sufficiently large number of experimental studies have shown that the system of endogenous opioids is closely related to the dopaminergic, and on par with the latter is directly involved in the formation of alcohol dependence. The bottom line is that alcohol, getting into the body under the action of alcohol dehydrogenase breaks down into a number of metabolites, the main of which is acetaldehyde. At the same time, alcohol causes the release of free dopamine from the depot . Condensation of acetaldehyde and dopamine produces a number of endogenous compounds of non-peptide structure: tetragidropapaveralin, salsolinol, tetrahydro-β-carboline. These condensation products of alcohol and dopamine are able to interact with opiate receptors of a brain and, thus, to show the properties of morphine [21]. So, that is why, according to modern views, naltrexone being a blocker of opiate receptors reduces euphoric and reinforcing effects of ethanol [22]. A significant number of double-blind, randomized, placebo-controlled clinical studies of naltrexone efficacy in alcohol dependence treatment have been conducted. The data are ambiguous. Certain contradictory in results is related to the relatively short periods of research (12 weeks). [9, 23, 24]. But longer (although numerically small) studies did not make sufficiently clear the final result [25, 26]. The majority of authors still note a slight increase in cases of complete abstinence from alcohol during naltrexone treatment, or at least, reducing the number of relapses after sporadic use of alcohol, as well as reducing amount of alcohol by individuals who continue to use it. The results of the cited studies [25] demonstrate the importance of combination of naltrexone therapy with regular counseling and cognitive-behavioral (or other kind of) psychotherapy. Along with the spread of the “American method” of continuous treatment with naltrexone there is a technique of Finnish researchers [27], based on the theory of repayment of Pavlov. According to this technique the patient is taking naltrexone only a few hours before the alleged use of alcohol. The authors believe that in these cases, naltrexone blocks the euphoric effect of alcohol and gradually “extinguishes” its reinforcing effect, which in its turn reduces the frequency and amount of alcohol consumption. Outside the situations involving alcohol intake, the patient, according to this method, does not take naltrexone. As in case of opioid addiction, naltrexone for alcohol addiction treatment is taken orally, once a day at the dose of 50 mg (although some data suggest the need to take not less than 100 mg a day). There is an evidence [28] that naltrexone for alcohol dependence treatment is only effective when the level of compliance is not less than 70-90% (daily intake of naltrexone is 100% compliance). Besides, it was recently demonstrated that naltrexone is most effective in patients with a specific subtype of opioid μ-receptor, which is determined by genetic analysis of alleles of the gene encoding this receptor [29]. Currently, the studies of so-called combination therapy (eg, pharmacotherapy and behavioral therapy), for alcohol dependence treatment are on the way, which allow us to specify the possibility of pharmacotherapy in general, as well as various combinations of treatment by naltrexone. So, in a double-blind, randomized, placebo-controlled study [25], which lasted 4 years and included the 1383 patients with alcohol dependence, studied the effectiveness of naltrexone, acamprosate, a standard cognitive-behavioral therapy (CBT) and their combinations . It was shown that naltrexone is more effective than placebo only in the absence of CPT. In case of CBT all other drugs and their combinations did not differ in effectiveness from each other, apparently due to the fact that CBT “overpassed ” the effect of the drugs. In this case, naltrexone reduced the risk of heavy drinking compared to placebo, reduced craving for alcohol, and also reduced the number of days of heavy drinking. Quality of life of patients treated with CBT was better than that of patients treated with the other therapy options . There is evidence that naltrexone can be effective in treatment for other types of addictions as well, namely: for nicotine dependence [30] and for γ-hydroxybutyric acid dependence (GHB) [31]. It is also known that naltrexone relieves kleptomania [32] and pathological gambling. It should be noted that the scope of potential use of naltrexone is not limited to states of dependence. Nowadays it is actively investigated the possibility of treatment with naltrexone deviant hypersexuality in adolescents [33], multiple sclerosis [34] and autism [35].


Prolong naltrexone as a means of addressing compliance. Vivitrol. As already mentioned, the main reason for reducing the effectiveness of naltrexone in treatment of addictions is a low compliance and high level of relapse after stopping treatment [15]. Three independent studies performed in 2000, 2001 and 2002 respectively (Fig. 4) showed that the number of patients continued to take naltrexone orally rapidly decreased in course of time. Moreover, about 50% of the total number of discharged patients who were on naltrexone never renewed a prescription for it, despite the free provision of medication.

naltrexone oral

Fig. 4. Dynamics of the patients stopped taking oral forms of naltrexone on the example of alcohol-dependent patients [cf. by Harris K. M. et al. / / Psychiatric Services. – 2004. – Vol. 55. – P. 221]. One method supposed to improve compliance is the use of depot forms of naltrexone, which do not require daily dosing. An example of such depot form of naltrexone is the form of pellets for implantation («prodetokson»- trade mark of Naltrexone implant. Russia), which is a combination of naltrexone at a dose of 1000 mg and triamcinolone for prevention of inflammation at the implant site [9, 36]. However, the implantation of a solid form is a minor surgery which requires appropriate conditions and qualified personnel. Much more convenient is the use of liquid pharmaceutical depot forms, allowing the usual intramuscular injections. At present, the most common injectable depot form of naltrexone is vivitrol. One bottle of vivitrol contains 380 mg of naltrexone in the form of microspheres (diameter approximately 100 microns). Microspheres is a slowly biodegradable polymer composed of polylactideko-glycolide (PPH) matrix with embedded active naltrexone. After injecting of vivitrol, naltrexone is being released from the microspheres, reaching peak concentration within 3 days (Fig. 5). Due to diffusion and resorption of the polymer matrix naltrexone stands in a body for more than 30 days [37, 38]. naltrexone plasma or injection vivitrol

Fig. 5. Dynamics of the concentration of naltrexone in the plasma when it is taken orally and when it is injected in form of Vivitrol [cf. by Dunbar J. L. et al. / / Alcoholism, Clinical and Experimental Research. – 2006. – Vol. 30, № 3. – P. 480-490] Due to the fact that the sufficient concentration in plasma remains relatively constant over the time, the pharmacological effects of vivitrol differ significantly from the similar effects of oral form of naltrexone. Effectiveness of naltrexone in treatment for alcohol dependence in sence of achievement and stabilization of remission was demonstrated in a double-blind, randomized trials [39]. It was shown that after six months of combined psychosocial therapy with Vivitrol the number of “drunks” days decreased by 22.8 times, compared with a baseline, and was 90% lower than with combined psychosocial therapy with placebo (Fig. 6 ).

Vivitrol treatment

Fig. 6. The number of the”drunk” days before treatment and after six months of psychosocial therapy with placebo and with Vivitrol treatment [cf. by O’Malley S. S. et al. / / Journal of Clinical Psychopharmacology. – 2007. – Vol. 279, № 5. – P. 507-512]. Convenient scheme of Vivitrol use is once in 4 weeks. It helps to solve the problem of compliance. According to a special study [39], 60% of patients were able to successfully complete the 24-week (168 days) Vivitrol treatment program. As shown by studies Vivitrol is generally well tolerated. In contrast to oral naltrexone the toxic effects of Vivitrol on the liver are not observed, which are probably associated with less synthesis of derivatives, including 6-beta-naltrexol by reducing presystemic metabolism in the liver, as well as the fact that the total monthly dose of naltrexone in vivitrol form (380 mg) is almost 4 times lower than in oral form of naltrexone (50 mg / day × 30 days = 1500 mg). Therefore Vivitrol can be used in patients with mild and moderate hepatic impairment (grade A and B in Child-Pugh). The most frequent adverse events in clinical trials were nausea, local reactions, and headache. Because the metabolism of Vivitrol occurs without the participation of cytochrome P-450, the influence of inducers and inhibitors of cytochrome on metabolism of Vivitrol is not expected. That effect of Vivitrol significantly reduces the risk of interactions with other drugs [39]. Analysis presented in this review of sources suggests that the creation of new inhibitors of opiate receptors and the development of new dosage forms develops in the direction of increasing the selectivity, reducing the number and severity of side effects and increasing the duration and ease of application. The main goal of this effort is to improve patients’ adherence with a substance abuse problem (especially with opioid and alcohol addiction) to treatmen and, ultimately to improve the quality of life of these patients. On set of properties, the apex of this evolution nowadays should be considered Vivitrol – prolong naltrexone in form of intramuscular injection.

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Linsky, A. Minko, V. Kuzminov, E. Samoilova, V. Goloshchapov, A.Minko. Made public by publication: Linsky I, Minko A., Kuzminov V., Samoilova E., Goloshchapov V., Minko A. From naloxone to vivitrol: opiate receptor blockers in clinical practice.


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