Structure-Bias Relationship of μ-Opioid Receptor Agonists.

Henrik Kehlet, MD, PhD† The review article by Brennan, Carr, and Cousins (1) is a laudable effort to discuss the ethical, political, cultural, and legal challenges involved in trying to improve the management of both acute and chronic pain. Unfortunately, this largely philosophical review fails to provide convincing scientific arguments to support the authors’ strongly held beliefs that many physicians fail to provide adequate pain relief because of a lack of concern and/or because of misconceptions regarding the use of analgesics in the management of pain (1–3). Although there is a clear need for improved techniques for controlling acute and chronic pain, we have serious concerns about the authors’ seemingly narrow focus on the alleged under-use of opioid analgesics and their suggestion that more liberal use of opioids can solve the problem. We would strongly argue for a more balanced view when considering approaches to improving acute and chronic pain management. Brennan et al. (1) are appropriately critical of the myths perpetuated by misinformed physicians. However, in characterizing individuals who advocate against more liberal use of opioid (narcotic) analgesics as “opioidphobic and/or opioignorant,” they demonstrate a disconcerting lack of insight into the recent literature relating to the frequent adverse effects associated with the use of opioid analgesics in the management of acute and chronic pain. Not only are opioid-related adverse drug events common in hospitalized patients, they increase the length of stay and total hospital cost (4,5). In reviewing the critical outcomes related to the use of opioids in the management of chronic noncancer pain, Eriksen et al. (6) recently concluded that long-term use of these compounds in the treatment of noncancer pain failed to improve the patients pain relief, quality of life or functional capacity. A recent study by Chu et al. (7) suggested that opioid tolerance and hyperalgesia develop within one month of initiating therapy with oral morphine in patients with chronic pain. Even short-term use of potent opioid compounds for acute pain can produce clinically significant hyperalgesia (8–10). Brennan et al. (1) state that the “under-treatment of pain is a poor medical practice that results in many adverse effects” and “is an abrogation of a fundamental human right.” Yet, they fail to provide scientific evidence from the peer-reviewed medical literature to support many of their statements regarding the alleged benefits of more aggressive approaches to acute and chronic pain management for patients, their families and society. Interestingly, in a recent issue of Anesthesia & Analgesia, Liu and Wu (11) performed a systematic review of the pain literature and concluded that evidence supporting improved outcomes due to better postoperative pain management is lacking. Although the methodology used by these investigators has been questioned (12), we would also strongly disagree with the conclusions of Brennan et al. (1) regarding the purported benefits of liberalizing the use of opioid analgesics in the management of pain. In fact, some clinical studies have suggested that use of large doses of opioid analgesics may contribute to increased morbidity and mortality in the acute care setting (13). Brennan et al. (1) have also completely From the *Department of Anesthesiology and Pain Management, University of TX Southwestern Medical Center at Dallas, Texas, †Section for Surgical Pathophysiology, The Juliane Marie Centre, Rigshospitalet, Copenhagen, Denmark. Accepted for publication April 10, 2007. Supported by Endowment funds from the Margaret Milam McDermott Distinguished Chair of Anesthesiology and the White Mountain Institute (to P.F.W.). Address correspondence and reprint requests to Paul F. White, MD, PhD, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9068. Address e-mail to paul.white@utsouthwestern.edu. Copyright © 2007 International Anesthesia Research Society DOI: 10.1213/01.ane.0000268392.05157.a8

IntroductionIn the USA, opioid analgesic use and overdoses have increased dramatically. One rapidly expanding strategy to manage chronic pain in the context of this epidemic is medical cannabis. Cannabis has...

Strategies for developing μ opioid receptor agonists with reduced adverse effects

human rights. 2– 4 Noticeable shifts in attitude have occurred in recent years regarding the use of opioids for the treatment of benign and malignancy-related pain. Primary care physicians and pain specialists prescribe opioids to a greater number of patients and in doses appropriate to needs. 3–7 A variety of opioid analgesics and delivery systems have been introduced that have increased patient satisfaction, physician acceptance, and overall use. Concomitant with improvements in pain relief and quality of life, an increasing number of patients are affected by issues related to opioid tolerance and physical dependence. There have been only a small number of published reviews that address the treatment of acute pain in patients with substance abuse disorders, 3–5 and fewer have focused specifically on perioperative pain management in opioid-dependent patients. 6,7 This review outlines factors responsible for opioid tolerance, physical dependence, and addiction and provides perioperative analgesic dosing guidelines for this specialized subset of patients. Many patients who present for surgery and anesthesia may be opioid dependent or at least moderately tolerant to the therapeutic effects of opioid analgesics. 5–7 Causal factors underlying dependency include substance use disorder and, more commonly, legitimate use of opioid analgesics for treatment of chronic benign pain or malignancy-associated pain. Perioperative management of opioid-dependent patients poses a special challenge to primary caregivers, anesthesiologists, and pain specialists alike. This problem emanates from the often-conflicting needs to balance the rights of the patient on one hand and concerns of safety, diversion, and abuse on the

Opioid analgesics are highly effective for treating many forms of acute and chronic pain. The development of opioid analgesic tolerance is a pharmacological phenomenon indicative of the cellular and system adaptation that could affect the clinical use of opioid analgesics. Activation of N-methyl-D-aspartate receptors and protein kinase C as well as regulation of glutamate transporters has been implicated in the mechanisms of opioid tolerance, suggesting a possible link between neural plasticity and the mechanisms of opioid tolerance. More recent studies have shown that neural plasticity associated with the development of opioid tolerance may activate a pronociceptive mechanism within the central nervous system that could counteract the analgesic effects of opioids. Thus, exposure to opioids could lead to two seemingly unrelated cellular processes, i.e. (1) the development of opioid tolerance--a negative sign of cellular adaptation, and (2) the development of opioid-induced pain sensitivity--a positive sign of cellular adaptation. The converging effects of these cellular mechanisms would significantly reduce the opioid analgesic efficacy. The current evidence also suggests new approaches for improving the clinical use of opioid analgesics.

Perioperative Opioid Analgesics and Hip Arthroscopy: Trends, Risk Factors for Prolonged Use, and Complications

Although μ-opioid receptor (MOR) agonists are the most effective drugs for relieving acute pain, nonselective activation of MOR can also lead to serious side effects. There is an urgent need for novel analgesics that can selectively activate MOR under pathological conditions while avoiding side effects under normal physiological conditions. In this study, a series of pH-sensitive 4-propionamide piperidine derivatives were synthesized and evaluated for their MOR activities and antinociceptive effects. Among them, compound 22 showed high pH sensitivity for MOR with a K ipH7.4/K ipH6.4 ratio of 6.6. Compound 22 acted as an MOR agonist in the functional test. Compound 22 exhibited good antinociceptive effects in the acetic acid-induced writhing test (ED50 = 1.5 mg/kg) and carrageenan-induced inflammatory pain model (ED50 = 3.3 mg/kg) in mice. Moreover, compound 22 showed reduced side effects when compared to the equianalgesic dose of fentanyl, including physical dependence, hyperlocomotion, and constipation. Compound 22 holds promise as a safe candidate for further development as an analgesic with diminished side effects.

Background: The epidemic of medical use and abuse of opioid analgesics is linked to the economic burden of opioid-related abuse and fatalities in the United States. Multiple studies have estimated the extent to which prescription opioid analgesics contribute to the national drug abuse problem; studies also assessing the trends in medical use and abuse of opioid analgesics have confirmed the relationship between increasing medical use of opioids and increasing fatalities. The available data is limited until 2002.. Study Design: Retrospective analysis of data from 2004 to 2011 from 2 databases: Automation of Reports and Consolidated Orders System (ARCOS) for opioid use data and Drug Abuse Warning Network (DAWN) for drug misuse data. Objective: To determine the proportion of drug abuse related to opioid analgesics and the various trends in the medical use and abuse of 8 opioid analgesics commonly used to treat pain: buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, and oxycodone. Methods: The data obtained from DAWN is a nationally representative sample of hospital emergency department admissions resulting from drug abuse. Main outcome measure was the identification of trends in the medical use and misuse of opioid analgesics from 2004 to 2011. Results: From 2004 to 2011, there was an increase in the medical use of all opioids except for a 20% decrease in codeine. The abuse of all opioids including codeine increased during this period. Increases in medical use ranged from 2,318% for buprenorphine to 35% for fentanyl, including 140% for hydromorphone, 117% for oxycodone, 73% for hydrocodone, 64% for morphine, and 37% for methadone. The misuse increased 384% for buprenorphine with available data from 2006 to 2011, whereas from 2004 to 2011, it increased 438% for hydromorphone, 263% for oxycodone, 146% for morphine, 107% for hydrocodone, 104% for fentanyl, 82% for methadone, and 39% for codeine. Comparison of opioid use showed an overall increase of 1,448% from 1996 to 2011, with increases if 690% from 1996 to 2004 and 100% from 2004 to 2011. In contrast, misuse increased more dramatically: 4,680% from 1996 to 2011, with increases of 1,372% from 1996 through 2004 and 245% from 2004 to 2011. The number of patients seeking rehabilitation for substance abuse also increased 187% for opioids, whereas it increased 87% for heroin, 40% for marijuana, and decreased 7% for cocaine. Limitations: Limitations of this assessment include the lack of data from 2003, lack of data available on meperidine, and that the aggregate data systems used in the study did not identify specific formulations or commercial products. Conclusion: The present trend of continued increase in the medical use of opioid analgesics appears to contribute to increases in misuse, resulting in multiple health consequences. Key words: Medical use of opioids, inappropriate use of opioids, abuse of opioids, opioid-related fatalities, Automation of Reports and Consolidated Orders System (ARCOS), Drug Abuse Warning Network (DAWN), International Narcotics Control Board (INCB)

BackgroundEULAR recommends the use of non-opioid oral medicines (acetaminophen, NSAIDs, or COX-2 inhibitors) for the management of knee osteoarthritis (OA). Opioids are also recommended when these other therapies fail. There...

Differential regulation of the μ-opioid receptor (MOP) has been linked to the development of opioid tolerance and dependence which both limit the clinical use of opioid analgesics. At a cellular level, MOP regulation occurs via receptor phosphorylation, desensitization, plasma membrane redistribution, and internalization. Here, we used fluorescence correlation spectroscopy (FCS) and fluorescence recovery after photobleaching (FRAP) to detect and quantify ligand-dependent changes in the plasma membrane organization of MOP expressed in human embryonic kidney (HEK293) cells. The low internalizing agonist morphine and the antagonist naloxone did not alter constitutive MOP plasma membrane organization. In contrast, the internalizing agonist DAMGO changed MOP plasma membrane organization in a pertussis toxin-insensitive manner and by two mechanisms. Firstly, it slowed MOP diffusion in a manner that was independent of internalization but dependent on GRK2/3. Secondly, DAMGO reduced the surface receptor number and the proportion of mobile receptors, and increased receptor clustering in a manner that was dependent on clathrin-mediated endocytosis. Overall, these results suggest the existence of distinct sequential MOP reorganization events at the plasma membrane and provide insights into the specific protein interactions that control MOP plasma membrane organization.

The clinical use of opioid analgesics, such as morphine, is limited by analgesic tolerance, molecular mechanism of which is not well understood. Recently, molecular chaperone heat shock protein 70 (Hsp70) has been demonstrated to play important roles in morphine-induced neuroadaptation. Here, we focused on the involvement of Hsp70 in the development of analgesic tolerance to morphine. Rats were treated with morphine (5, 10, 20 mg/kg, subcutaneously) or saline once daily for 10 consecutive days. Hsp70 modulator N-formyl-3, 4-methylenedioxybenzylidine-γ-butyrolactam [KNK437, 100 mg/kg, intraperitoneally (i.p.)], geranylgeranylacetone (500 mg/kg, i.p.) or pifithrin-μ (20 mg/kg, i.p.) was administered before morphine (10 mg/kg, subcutaneously)/saline treatment. Analgesic effect of morphine was measured using the tail-flick latency test, and Hsp70 protein expression was examined by western blot. Analgesic effect of morphine decreased gradually with the increase in the number of days of morphine injection, indicating development of analgesic tolerance. A significant increase of Hsp70 expression in the periaqueductal gray was observed during the development of analgesic tolerance after repeated morphine injections. The development of morphine analgesic tolerance was suppressed by pre-treatment with Hsp70 transcriptional inhibitor KNK437 or functional antagonist pifithrin-μ, while promoted by pre-treatment with Hsp70 transcriptional inducer geranylgeranylacetone. Our results demonstrated that the development of morphine analgesic tolerance was dual regulated by Hsp70 modulators, suggesting Hsp70 as an interesting and new target for preventing the development of opioid analgesic tolerance.

Therapeutic Interactive Voice Response (TIVR) to Reduce Analgesic Medication Use for Chronic Pain Management

In Europe and France, the use of opioid analgesic drugs has become widespread as an option for pain management. However, their use can lead to nonmedical use and/or opioid use disorder (OUD). This work aimed to assess the perceived risk of OUD secondary to opioid analgesic drugs use by the general population. We conducted a cross-sectional observational study using the GrippeNet web-based cohort, comprising about 10,000 French volunteers from the general population, using a self-administered questionnaire. The main outcome was the perceived risk of OUD secondary to opioid analgesic drugs use, assessed by a 4-item scale and modelled using logistic regression (backward procedure). Among 5046 French respondents, after adjustment, 65% believed that the use of analgesic drugs could likely or very likely lead to OUD. Factors associated with the perception of a higher risk were being over 50 and having heard about opioids in the media. Previous opioid use and a high level of education decreased the perception of the risk. Among those having used opioids in the past 2years (N=1770), 71.1% reported being not at all concerned by this risk. The majority of the sample perceived the risk of OUD but those having already used opioid analgesics drugs expressed no concern about this risk for themselves. This finding highlight the need to reinforce warning on the package insert documents, therapeutic education and collaborative care between the prescribing general practitioners and pharmacists to increase awareness of opioid medications users on the risk of OUD. This study found that the risk of OUD secondary to opioid analgesics use is well perceived in the general population, but that those having already used opioid analgesics expressed little concern for themselves. This finding could potentially help to raise awareness of healthcare providers and policy makers on the lack of perceived risk regarding these drugs and the need to inform and identify at-risk patients in primary care.

Recent results suggests the risk of a new onset of depression increases with longer duration of opioid analgesic use. It is unclear whether new-onset depression related to opioid analgesic use is a function of the dose prescribed or the duration of use or both. Using a retrospective cohort design, we collected patient data from 2000 to 2012 from the Veterans Health Administration (VHA), and from 2003 to 2012 from both Baylor Scott & White Health (BSWH) and the Henry Ford Health System (HFHS). Patients (70,997 VHA patients, 13,777 BSWH patients, and 22,981 HFHS patients) were new opioid users, aged 18 to 80 years, without a diagnosis of depression at baseline. Opioid analgesic use duration was defined as 1 to 30, 31 to 90, and more than 90 days, and morphine equivalent dose (MED) was defined as 1 to 50 mg/d, 51 to 100 mg/d, and greater than 100 mg/d of analgesic. Pain and other potential confounders were controlled for by inverse probability of treatment-weighted propensity scores. New-onset depression after opioid analgesic use occurred in 12% of the VHA sample, 9% of the BSWH sample, and 11% of the HFHS sample. Compared with 1- to 30-day users, new-onset depression increased in those with longer opioid analgesic use. Risk of new-onset depression with 31 to 90 days of opioid analgesic use ranged from hazard ratio [HR] = 1.18 (95% CI, 1.10-1.25) in VHA to HR = 1.33 (95% CI, 1.16-1.52) in HFHS; in opioid analgesic use of more than 90 days, it ranged from HR = 1.35 (95% CI, 1.26-1.44) in VHA to HR = 2.05 (95% CI, 1.75-2.40) in HFHS. Dose was not significantly associated with a new onset of depression. Opioid-related new onset of depression is associated with longer duration of use but not dose. Patients and practitioners should be aware that opioid analgesic use of longer than 30 days imposes risk of new-onset depression. Opioid analgesic use, not just pain, should be considered a potential source when patients report depressed mood.

The paradox of decreasing nonmedical opioid analgesic use and increasing abuse or dependence — An assessment of demographic and substance use trends, United States, 2003–2014