Opioid Pharmacology Research Articles

Urine Toxicology Testing in Chronic Pain Management

Treatment guidelines for chronic noncancer pain recommend opioids for carefully selected, closely monitored patients. However, many primary care physicians have a limited understanding of urine toxicology testing, which is the standard for monitoring opioid therapy. This article describes the technical aspects of urine toxicology testing and provides recommendations for monitoring patients to maximize the safety of opioid therapy. Articles were identified in PubMed, Medline, and EMBASE (January 1980–November 2008) using the search term opioid in combination with the terms urine toxicology, compliance monitoring, abuse, and diversion. Articles characterizing the pharmacology of individual opioids and practice guidelines for the management of chronic pain were also identified. Articles selected for inclusion discussed technical aspects of urine toxicology testing, clinical aspects of monitoring, and issues related to abuse and diversion. Urine tests can detect prescribed and illicit substances that are present above a specific threshold, but they provide limited data about the source, dose, or route of administration of substances detected. Effective monitoring requires careful test selection, an understanding of pharmacologic and metabolic factors influencing test results, and awareness of methods by which patients who are substance abusers may tamper with test specimens to escape detection. All patients prescribed opioids, not just those considered at risk for abuse, should undergo urine toxicology testing. Given its inherent complexities, effective urine testing requires close collaboration between the primary care physician and a reliable laboratory to develop an appropriate test protocol for each patient and to interpret test results.

Utilizing Nature as a Source of New Probes for Opioid Pharmacology

Traditional and current opioid pharmacology is fundamentally based on interactions between opioid receptors and compounds isolated from natural sources. Adverse effects associated with opioids have led to the search for compounds with diminished side effects. Recent discoveries of non-nitrogenous and structurally diverse alkaloids as novel opioid ligands have led to renewed interest in the development of novel chemotypes for opioid receptors. The strong history of natural products as opioid receptor ligands suggests that nature is one of the most promising for the identification of novel opioids. This review highlights the vast potential of investigating natural products as novel probes of opioid receptors.

Critical Thinking in Anesthesia

Critical Thinking in Anesthesia

Respiratory and Sleep Effects of Remifentanil in Volunteers with Moderate Obstructive Sleep Apnea

There is concern that opioid-based analgesia will worsen sleep-related respiratory insufficiency in patients with obstructive sleep apnea (OSA), resulting in serious morbidity or mortality. However, there are no studies that directly address the merit of this concern. Consequently, the authors designed this study as the first prospective, double-blind, placebo-controlled investigation of opioid pharmacology in patients with documented OSA. Patients (n = 19) with moderate OSA documented by polysomnography (sleep study) were randomized to undergo an additional sleep study while receiving either a saline infusion or a remifentanil infusion (0.075 microg x kg x h). Sleep stages, apneas, hypopneas, and arterial hemoglobin oxygen saturation were continually recorded during saline or remifentanil infusion, and were compared with values obtained during the patients' earlier sleep study. Saline infusion had no effect on sleep or respiratory variables. In contrast, remifentanil increased Stage 1 sleep, markedly decreased rapid eye movement sleep, increased arousals from sleep, and decreased sleep efficiency. Remifentanil actually decreased the number of obstructive apneas, but markedly increased the number of central apneas. Arterial hemoglobin oxygen saturation was also significantly lower in OSA patients receiving remifentanil. The decrease in obstructive apneas likely resulted from the marked decrease in rapid eye movement sleep caused by remifentanil. Despite fewer obstructions, OSA was worse during remifentanil infusion because of a marked increase in the number of central apneas. These data suggest that caution is warranted when administering opioids to subjects with moderate OSA, but that the primary risk may be central apnea, not obstructive apnea.

Design, Synthesis, and Evaluation of Biotinylated Opioid Derivatives as Novel Probes to Study Opioid Pharmacology

A generally applicable strategy of chemically labeling (-)-morphine (1) is described. The synthesis starts from commercially available starting materials and can be completed in two steps with an overall yield of 23%. In silico simulation and NMR results show that the binding of (-)-morphine to one of its molecular targets, toll-like receptor 4 (TLR4), was not affected by the modification. Secreted embryonic alkaline phosphatase (SEAP) reporter assay results demonstrate that C(3) biotinylated and unmodified (-)-morphine show similar biological activities in live cells. To our knowledge, these studies provide the first practical and concise method to label various opioid derivatives, a group of important therapeutics in pain management, for biochemical/pharmacological studies.

Synthesis, opioid receptor binding profile and SAR studies of 14-alkoxy-substituted indolo- and benzofuromorphinans

On the basis of pharmacological, behavioral and biochemical studies, opioid receptors have been classified into three major types, μ, δ and κ, belonging to the family of the G protein-coupled receptors. All three receptor types are expressed in the central and peripheral nervous systems of both animals and human. Receptor type selective opioid agonists and antagonists are of interest both as pharmacological tools and as potential therapeutic agents for the treatment of pain, addiction, constipation or immunological diseases. During the past 3 decades, one of the major aims of medicinal chemistry and opioid pharmacology has been to develop opioids with high affinity and/or selectivity for each of the three receptor types. In this study, 14-alkoxy analogues of naltrindole, naloxindole and naltriben with different benzyloxy substitution in position 14 have been investigated to elaborate on structure-activity relationships (SAR) of the morphinan class of compounds. To this aim, several 14-benzyloxy substituted indolo- and benzofuromorphinans were prepared by multi-step synthesis using naloxone and naltrexone as starting materials. Binding affinities and selectivities to opioid receptors (μ, δ and κ) were determined using in vitro binding assays with rodent brain membranes employing selective opioid radioligands. Examination of the chemical structure and opioid binding profile i.e. affinities and selectivities reveals certain SAR for the investigated compounds. Opioid binding affinity was sensitive to the character and length of the substituent in position 14. Introduction of 14-benzyloxy groups resulted in reduced affinity and selectivity for the δ receptor. The replacement of the N-allyl by an N-cyclopropylmethyl group in position 17 resulted in increased δ affinity without affecting δ receptor selectivity. The results of the present study indicate that position 14 of indolo- and benzofuromorphinans represents a critical site that could be a trigger to develop opioid compounds with increased δ affinity and/or selectivity. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors.

5-Benzyl substituted 14-methoxymetopon, a high affinity μ opioid receptor agonist with potent antinociceptive activity in mice

Pain constitutes a major public-health problem with an impact on both the individual and the society that is still inadequately treated. All clinically used opioid analgesics for severe acute and chronic pain, e.g. morphine, fentanyl and oxycodone, are agonists activating central μ opioid receptors. Their clinical use is associated with a number of adverse actions, such as respiratory depression, sedation, nausea, constipation, tolerance and addiction. One of the major aims of medicinal chemistry and opioid pharmacology is to develop opioids with high affinity and/or selectivity for the μ opioid receptor, exhibiting a favorable dissociation between analgesia and the occurrence of side effects. 14-Methoxymetopon, designed by our group, was described as a highly potent and selective μ opioid agonist with an unusual pharmacological and functional profile, being genuinely safer than the gold standard pain-killer morphine. With the aim to identify and develop scientifically proven opioid drugs with a reliable target-oriented pharmacological profile, established efficacy and favorable safety index, a new analogue of 14-methoxymetopon, containing a benzyl substituent at position 5, was investigated for its in vitro biological and in vivo pharmacological activities. Binding affinities and selectivities to opioid receptors were determined in rodent brain membranes using competition binding assays. Analgesic activity after subcutaneous (s.c.) administration was assessed in mice using tail-flick and hot-plate tests. The rotarod test was used to evaluate the drug effect on motor coordination. In vitro binding studies indicated that the 5-benzyl analogue of 14-methoxymetopon displayed high affinity and selectivity at the μ opioid receptor. It showed a significant increase in affinity (20-fold) at the μ receptor as compared to that of morphine. The 5-benzyl derivative produced dose-dependent analgesic effects in the tail-flick and hot-plate tests after s.c. administration to mice. The antinociceptive dose necessary to elicit a 50% effect (ED50) was 43 μg/kg in the tail-flick test and 53 μg/kg in the hot-plate test. Compared to 14-methoxymetopon, the new analogue showed comparable antinociceptive potency, while it was about 50-fold more active than morphine. No significant impairment of the motor performance was induced by the novel opioid. These findings show that introduction of a 5-benzyl substituent into 14-methoxymetopon did not significantly affect the in vitro and in vivo pharmacological properties compared to the parent compound. The interesting pharmacological profiles of this class of morphinans will serve as a basis for our continuing exploration of potent opioid analgesics for the pharmacotherapy of pain.

ChemInform Abstract: Salvinorin A Analogues as Probes in Opioid Pharmacology

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Intrathecal opioids in the management of acute postoperative pain

In 1968, Melzack and Wall put forward their ‘gate control theory’ proposing that the spinal cord was a potential target site for modulation of pain signals. This changed our concepts about nociceptive transmission and laid the foundation for further research into dorsal horn opioid pharmacology. This led to the discovery of opioid receptors by Pert and Snyder in 1973 and the subsequent identification of dorsal horn opioid receptors by radioligand techniques in 1977. Yaksh went on to demonstrate that opioids modulate nociceptive stimuli via a direct action on the spinal cord in 1976. Wang was the first to describe the intrathecal administration of morphine in a group of eight patients with genitourinary malignancies in 1979. Since that time, the use of intrathecal opioids has become a widely accepted technique for providing effective postoperative pain relief. The changing health economy has driven the need for greater patient throughput, rapid turnover and shorter hospital stays whilst retaining high quality medical care. The combination of intrathecal analgesia with minimally invasive surgery has led to the development of accelerated surgical care pathways. This review will focus on the use of intrathecal opioids in the acute postoperative pain setting.

Salvinorin A analogs as probes in opioid pharmacology.

The opium poppy, Papaver somniferum, is one of several plants that have profoundly affected human history.1 It has provided an unmatched medicine for the relief of pain for centuries.2 More than 30 alkaloids have been identified in opium, and among the most relevant are morphine (1a) and codeine (1b) (Figure 1).3 These alkaloids are important for modern medicine as an analgesic and a cough suppressant, respectively. These and related opiates exert their pharmacological effects by interacting with opioid receptors.4

The chemical and pharmacological importance of morphine analogues

The object of this review is to summarize the efforts which resulted in the discovery of therapeutically useful morphine-like drugs. The search for new analgesics can be divided into three stages: (a) search for analgesics with high efficacy and reduced unwanted side-effects; (b) understanding of structure-activity relationships; (c) studies on the mechanism of pain perception and its alleviation by investigation of the pharmacology of opioids. An immense body of literature has been produced on the syntheses of thousands of new compounds which resulted in the development of detailed structure-activity relationships. The physical and psychologic dependence of opioid analgesics also facilitated investigators to solve the problem of the separation of strong analgesia from addiction liability. In the past decades more mixed agonist-antagonist analgesics, pure antagonists devoid of agonist action and potent opioids like the 6,14-ethenomorphinan derivatives were developed. Naloxone, Naltrexone, Buprenorphine and Pentazocine are the outstanding representatives which are introduced into clinical therapy.

Role of pharmacogenetics in variable response to drugs: focus on opioids

Pharmacogenetics is the study of the role of genetics in inter-individual variability to drug response and therapy. This review provides a comprehensive report of the present status of pharmacogenetic studies for opioid drugs. Opioid analgesics are widely used clinically for pain management, and inter-patient variability with opioid therapy is often reported. Information on genetic polymorphisms in enzymes, receptors and transporters related to opioid disposition (pharmacokinetics) and pharmacology (pharmacodynamics) is discussed. Pharmacogenetics of enzymes, including the cytochrome P450s and uridine diphosphoglucuronosyltransferases, opioid receptors and the ABC family of transporters, is reviewed. The role of genetic variability in clinical opioid therapy is examined, and relevant clinical trials cited. The present status of opioid pharmacogenetics, promises and challenges and future directions are discussed.

Methylnaltrexone Mechanisms of Action and Effects on Opioid Bowel Dysfunction and Other Opioid Adverse Effects

To review the mechanisms of action of methylnaltrexone and its effects on opioid bowel dysfunction, as well as its effects on other opioid-induced adverse effects (ADEs), and its potential roles in clinical practice. A literature search using the MEDLINE and Cochrane Collaboration databases for articles published between 1966 and March 2007 was performed. Additional data sources were obtained from manual searches of recent journal articles, book chapters, and monographs. An updated literature search showed no additional publications. Abstracts and original preclinical and clinical research reports published in the English language were identified for review. Review articles, commentaries, and news reports of this compound were excluded. Literature related to opioids, opioid receptors, opioid antagonists, methylnaltrexone, opioid-induced bowel dysfunction, constipation, nausea, and vomiting was evaluated and selected based on consideration of the support shown for the proof of concept, mechanistic findings, and timeliness. Fifty-eight original articles from preclinical studies and clinical trials using methylnaltrexone were identified. Pharmacologic action, benefits, and ADEs of methylnaltrexone were reviewed, with a focus on its effects on bowel dysfunction after opioids. Emphases were placed on its receptor binding activities and therapeutically relevant sites of action (peripheral vs central), in which peripheral opioid receptors in the body contribute to physiological and drug-induced effects. Morphine and related opioids are associated with a number of limiting ADEs, including opioid-induced bowel dysfunction. Methylnaltrexone, a quaternary derivative of naltrexone, blocks peripheral effects of opioids while sparing central analgesic effects. It is currently under late-stage clinical investigation for the treatment of opioid-induced constipation in patients with advanced illness. Reported results showed the drug to be generally well-tolerated. The rapid reversal of constipation is very encouraging. Hastening postoperative discharge may also be possible. Methylnaltrexone has the potential to prevent or treat opioid-induced peripherally mediated ADEs on bowel dysfunction without interfering with central analgesia. The study of methylnaltrexone leads to a greater understanding of the mechanisms of action of opioid pharmacology.

A review of methylnaltrexone, a peripheral opioid receptor antagonist, and its role in opioid-induced constipation

Opioid medications are frequently used in pain and palliative care patients with malignancy to manage symptoms such as pain and dyspnea. However, opiates are associated with various side effects. Constipation is a particularly problematic and common side effect of opioid pharmacology. Opioid antagonists have been studied in the management of opioid-induced constipation. Methylnaltrexone (MNTX) is a peripheral opioid antagonist currently under clinical investigation. It offers the potential to reverse undesirable side effects without reversing analgesia. This article attempts to review existing clinical data, focusing on antagonism of opioid-induced adverse effects on the gastrointestinal system. MNTX seems to be well tolerated with limited or transient side effects. MNTX has been shown to improve oral-cecal transit times in opioid treated patients, induce laxation in chronic opioid users, and neither reverses the analgesic effects of morphine nor cause withdrawal symptoms. Larger clinical trials of MNTX are still necessary to support its use as a standard for treatment of opioid-induced constipation.

Effects of chronic opioid exposure on guinea pig mu opioid receptor in Chinese hamster ovary cells: Comparison with human and rat receptor

Chronic opioid treatment leads to agonist-specific effects at the mu opioid receptor. The molecular mechanisms resulting from chronic opioid exposure include desensitization, internalization and down-regulation of membrane-bound mu opioid receptors (MOP). The purpose of this study was to compare the cellular regulation of guinea pig, human and rat MOP expressed in Chinese hamster ovary (CHO) cells, following exposure to two clinically important opioids, morphine and methadone. MOP expressing CHO cells were treated in culture with methadone or morphine for up to 48 h. Radioligand diprenorphine and [ d-AIa 2, N-Me-Phe 4,Gly 5-ol]-enkephalin (DAMGO)-stimulated GTPγS binding assays were carried out using paired control and opioid-exposed CHO cells. Methadone induced downregulation of the mu opioid receptor, while morphine induced desensitization of the receptor for all three species. Furthermore, morphine predominantly decreased the potency of DAMGO to stimulate GTPγS binding, whereas methadone primarily reduced its efficacy. Changes in DAMGO potency and efficacy differed among species and depended on the opioid used to treat the cells. Our results showed similarities between guinea pig and human MOP for morphine-induced desensitization, but identified differences between the two for methadone-induced desensitization. In contrast, human and rat MOP differed in response to morphine treatment, but were not distinct in their response to methadone treatment. The guinea pig is an excellent and established animal model to study opioid effects, but its molecular opioid pharmacology has not been investigated thus far. These results can assist in understanding species differences in the effects of opioid ligands activating the mu opioid receptor.

Cholestasis and Endogenous Opioids

A class of endogenous opioids is upregulated in liver disease particular to cholestasis, which contributes to symptoms in liver disease such as pruritus, hypotension and encephalopathy. Symptoms associated with cholestasis are reversed or at least ameliorated by mu opioid receptor antagonists. Palliation of symptoms related to cholestatic liver disease also involves bile acid binding agents. Opioid receptor antagonists, unlike bile acid binding agents, have been reported to relieve multiple symptoms, except for pruritus, and improve liver function as demonstrated in experimental cholestasis. Exogenous opioid pharmacology is altered by liver disease. Dose reduction or prolongation of dose intervals is necessary depending on the severity of liver disease.

Ethical and Practical Issues with Opioids in Life-Limiting Illness

Effective pain relief, especially at the end of life, is a primary ethical obligation based upon the principles of beneficence, nonmaleficence, patient autonomy, and particularly the concept of double effect. The pragmatic foundation of pain management begins with a complete assessment, which incorporates “WILDA” (words, intensity, location, duration, aggravating/alleviating factors) and considers the components of total pain: physical, emotional, social, and spiritual pain. Opioids are the pharmacologic sine qua non of pain management in life-limiting illness and should be prescribed based on the severity of pain, considering the functional and psychological significance of that severity. Numerous misunderstandings present a barrier to effective pain management. These misconceptions include the idea that opioids are highly addictive, that dependence or tolerance are forms of addiction, that respiratory depression is common with opioids, that opioids have a narrow therapeutic range, and that opioids are ineffective by mouth and cause too much nausea. In reality, opioids are the safest and most effective pain medicine for most moderate to severe pain in most patients. Aspects of basic opioid pharmacology, such as dosage, route of administration, rotation of drugs, and the avoidance of toxicity and complications, should be considered when initiating and maintaining therapy. Failure to pay attention to the basic rules can lead to errors in opioid management.

Extended-release opioids for the management of chronic non-malignant pain

Recent clinical trials have documented the use of extended-release (ER) opioids in the management of chronic non-malignant pain. This manuscript reviews the clinical pharmacology of investigational and current marketed ER opioids. Recent randomised clinical trials of ER opioids that document the efficacy and safety of opioid therapy for chronic pain are reviewed. Finally, the abuse liability of ER opioids is discussed. Current technologies aimed at defeating the abuse of ER opioids will also be presented.

Oncologists practice with opioids in cancer pain

18602 Background: The majority of cancer patients are mostly under the care of their primary oncologists for both active and symptom management. Pain is the most feared symptom in cancer patients. In general, it is highly prevalent and under treated. Barriers to adequate pain management still exist even among specialized care givers. Improper opioid utilization is one of main factors within those impediments. The pattern of opioid prescription among oncologists in a specialized hospital was examined on referral to a palliative care unit within the same institution. Methods: Over a period of six months (between Dec. 2003 and June 2004) 290 cancer patients were referred to the section of palliative medicine from different medical specialties within the same institution. The medical records of 233 (80%) were analyzed, 116(50%) were referred from oncology specialists (radiation, medical & hematology oncology), 76 referred patients fulfilled the study criteria. On referral; all eligible patients had to be on opioids for pain. The pattern of opioid prescription by oncologists in this group of patients with reference to the currently available guidelines was examined. Results: The following results were found: Pain was inadequately controlled in 71% patients. Although, the majority of the patients 92% were able to utilize the oral route, it was only used in 36% of patients. The first strong regular opioid was the standard morphine in only 46% of patients. Breakthrough opioid was prescribed to most patients (91%). However, dose and interval were outside the general guidelines in 44% & 81% respectively. Laxatives were not prescribed in half of the patients Conclusions: Opioids are the principal effective, relatively simple and practical drugs in pain relief. Yet, within specialized care providers as shown in this study, opioid utilization was unsatisfactory. More understanding of pain assessment, better opioid utilization and more knowledge of opioid pharmacology still warranted. No significant financial relationships to disclose.

Wall and Melzack???s Textbook of Pain, 5th E-dition.

Wall and Melzack???s Textbook of Pain, 5th E-dition.