Delta-opioid receptors as targets for migraine therapy.

PURPOSE OF REVIEW: The purpose of this review is to contrast the properties of the δ-opioid receptor with those of the µ-opioid receptor, which is the primary target of most currently available opioid analgesics. We also discuss preclinical evidence that indicates the potential efficacy of δ-opioid receptor agonists as migraine therapy. RECENT FINDINGS: The use of currently available opioid analgesics is highly problematic for patients with migraine. Delta-opioid receptors have key differences from µ receptors; these differences make the δ receptor an attractive therapeutic target for migraine. Delta-opioid receptors are expressed in both the peripheral and central nervous system in anatomical regions and cell types that are believed to play a role in migraine. Delta-receptor agonists have also shown promising effects in multiple migraine models, including nitroglycerin evoked hyperalgesia and conditioned place aversion, and cortical spreading depression. Evidence from animal models indicates that activation of δ receptors is less likely to cause tolerance and dependence, and less likely to cause hyperalgesia. In addition, δ receptors may have antidepressant and anxiolytic properties that are distinct from those of µ receptors. In human studies investigating other conditions, δ-receptor agonists have been generally safe and well tolerated. SUMMARY: Delta-opioid receptor agonists have promising potential as acute and/or preventive migraine therapies, without the problems associated with currently used opioid analgesics.

Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study.

BACKGROUND & AIMS: Simultaneous agonism of the µ-opioid receptor and antagonism of the δ-opioid receptor can reduce abdominal pain and diarrhea in patients with irritable bowel syndrome with diarrhea (IBS-D) without constipating side effects. We evaluated the efficacy and safety of a minimally absorbed, µ-opioid receptor agonist and δ-opioid receptor antagonist (eluxadoline) in a phase 2 study in patients with IBS-D. METHODS: We randomly assigned 807 patients to groups that received oral placebo twice daily or 5, 25, 100, or 200 mg oral eluxadoline for 12 weeks. The primary end point was clinical response at week 4, defined by a mean reduction in daily pain score from baseline of ≥ 30%, and of at least 2 points on 0-10 scale, as well as a stool consistency score of 3 or 4 on the Bristol Stool Scale (1-7) for at least 66% of daily diary entries during that week. RESULTS: Significantly more patients receiving 25 mg (12.0%) or 200 mg (13.8%) eluxadoline met the primary end point of clinical response than patients given placebo (5.7%; P < .05). Patients receiving eluxadoline at 100 mg and 200 mg also had greater improvements in bowel movement frequency and urgency, global symptoms, quality of life, and adequate relief assessments (P < .05). Additionally, patients receiving 100 mg (28.0%) or 200 mg (28.5%) eluxadoline were significantly more likely than those receiving placebo (13.8%; P < .005) to meet the US Food and Drug Administration response end point during the full 12 weeks of the study. Eluxadoline was well tolerated with a low incidence of constipation. CONCLUSIONS: In a phase 2 study of the mixed µ-opioid receptor agonist/δ-opioid receptor antagonist eluxadoline vs placebo in patients with IBS-D, patients given eluxadoline were significantly more likely to be clinical responders, based on a composite of improvement in abdominal pain and stool consistency. Further study of eluxadoline is warranted to assess its potential as a treatment for IBS-D.

Recent advances in the opioid mu receptor based pharmacotherapy for rheumatoid arthritis.

INTRODUCTION: Opioids are used for severe forms of acute and cancer pain. Over the last years, their potential use in patients with noncancer pain such as those with rheumatoid arthritis (RA) has been postulated. A recent population-based comparative study showed that chronic opioid use was 12% vs. 4% among RA and non-RA patients, respectively. Another study showed an increase from 7.4% to 16.9% (2002 to 2015). In general, there has been an increasing tendency to use opioids in recent years. AREAS COVERED: The authors have performed an extensive literature search using PubMed for articles including noncancer pain and the use of the mu opioid receptor (MOR) agonists in patients with RA. EXPERT OPINION: Data is not sufficient to support opioid use for the treatment of chronic pain in patients with RA. Data is scarce and inconclusive. Rheumatologists should think and ponder the question: Why is this patient in pain? Differential diagnosis should include a disease flare, degenerative changes of the musculoskeletal system, and fibromyalgia. And while there are new strategies for opioid administration currently being researched, unfortunately, they are far from being applied to human subjects in the everyday clinical setting, and are still being evaluated at an experimental level. CNS: Central nervous system; DORs: delta opioid receptor agonists; GI: Gastrointestinal; GPCRs: G protein-coupled receptors; IL: Interleukin; JAK: Janus kinase; KORs: kappa opioid receptor agonists; MCPs: Metacarpophalangeal joints; MORs: Mu opioid receptor agonists; MTPs: Metatarsophalangeal joints; NSAIDs: Non-steroidal anti-inflammatory drugsOA: Osteoarthritis; ORs: Opioid receptors; PD: Pharmacodynamic; PIPs: Proximal interphalangeal joints; PK: Pharmacokinetic; PNS: Peripheral nervous system; RA: Rheumatoid arthritis; RGS: Regulator of G protein signaling; SSRIs: Selective serotonin reuptake inhibitors; TNF: Tumor necrosis factor.

Remifentanil and other opioids.

Most opioids used in anaesthesia are of the anilidopiperidine family, including fentanyl, alfentanil, sufentanil and remifentanil. While all share similar pharmacological properties, remifentanil, the newest one, is probably the most original, which is the reason this review focusses especially on this drug. Remifentanil is a potent mu-agonist that retains all the pharmacodynamic characteristics of its class (regarding analgesia, respiratory depression, muscle rigidity, nausea and vomiting, pruritus, etc.) but with a unique pharmacokinetic profile that combines a short onset and the fastest offset, independent of the infusion duration. Consequently, it offers a unique titratability when its effects need to be quickly achieved or suppressed, but it requires specific drug delivery schemes such as continuous infusion, target-controlled infusion and anticipated postoperative pain treatment. Kinetic differences between opioids used in anaesthesia and some clinical uses of remifentanil are reviewed in this chapter.

Understanding how opioids contribute to reward and analgesia.

Opioids acting at the mu opioid (MOP) receptor produce powerful analgesia. They also produce an intensely rewarding effect that can lead to addiction. The analgesic effect of MOP receptor agonists derives from a direct inhibitory effect on pain transmission at the spinal-cord level and through activation of a descending pain-modulatory pathway. The rewarding effect of MOP agonists is the result of their actions in the mesostriatal dopamine pathway classically associated with both natural and drug rewards. Both the analgesic and rewarding effect of MOP agonists are best understood in the context of decision making under conditions of conflict. Pain is one of many competing motivational states, and endogenous opioids suppress responses to noxious stimuli in the presence of conflicting motivations, such as hunger or a threatening predator. When a food reward is available, MOP agonists microinjected into the mesostriatal circuit promote its consumption, while concomitantly suppressing responses to noxious stimulation. The mesostriatal "reward" circuit, thus, appears to perform a function critical to decision making and can either amplify or suppress responses to noxious stimuli.

The Abuse Potential of Prescription Opioids in Humans-Closing in on the First Century of Research.

While opioids are very effective analgesics for treating acute pain, humans have struggled with opiate addiction for millenia. An opium abuse epidemic in the early 1900's led the US government to develop a systematic research infrastructure and scientific plan to produce new compounds with analgesic properties but without abuse liability. This review describes the techniques that were developed for testing in the human laboratory, including empirically derived outcome measures and required elements for human abuse potential assessment. The evaluation and characterization of semi-synthetic and synthetic opioids, including full mu opioid agonists, partial agonists and mixed agonist-antagonists, are described across several decades of research. Finally, the prescription opioid epidemic beginning in the 1990's in the US led to a resurgence in abuse potential evaluations, and the application of these methods to the study of novel abuse-deterrent formulations is discussed.

[Conversion to tapentadol PR improves analgesia and quality of life in patients with severe and chronic pain despite using tramadol > 300 mg/d]. / Konsekutive Umstellung auf Tapentadol PR verbessert Analgesie und Lebensqualität bei Patienten mit starken und chronischen Schmerzen unter Tramadol > 300 mg/d.

STUDY OBJECTIVE: This subgroup analysis of a non-interventional study involving general practitioners and internists investigated the administration of tapentadol PR (prolonged release) in patients with widely-utilized tramadol pretreatment in routine clinical practice in Germany. METHODS: Data of all patients in the study cohort who had tramadol as the only opioid in their previous therapy were included in the analysis (n = 685); among them especially the 99 patients with tramadol dosages exceeding 300 mg/d were focused. Data collection during the 3-month observation period included previous and concomitant analgesic treatment, tapentadol PR dosage, pain intensity, sleep and quality of life parameters, and tolerability of tapentadol PR. RESULTS: Back pain was the most common cause of pain (n = 86/99), other pain diagnoses were (partly additionally) recorded in 68 cases. A mixed type of pain dominated. The previous tramadol therapy was usually combined with non-opioids (n = 74), co-analgesics (n = 44) and analgesic rescue medication (n = 35). Tapentadol PR therapy reduced the mean initial pain intensity of 7.3 ± 1.5 to 3.1 ± 1.8 points (NRS-11, 11-point pain scale, n = 96) at the end of observation, using an average dosage of 218.7 mg/d. Tapentadol PR was finally applied as the sole analgesic in 32/95 patients. 69/96 patients achieved a clinically meaningful pain relief of at least 50 %, while 63 patients gained a pain reduction of ≥ 4 NRS-points. 89/95 patients reached or exceeded their additional individual treatment goal. This was accompanied by a significant decrease in pain-related impairments of daily activities and an improvement in quality of life with an overall good tolerability of tapentadol PR. Treatment with tapentadol PR was assessed positively by physicians and patients. CONCLUSIONS: Data analysis shows a clinically relevant benefit in patients unsuccessfully pretreated with tramadol by consecutive conversion to the potent analgesic tapentadol PR.

Combating opiate dependence: a comparison among the available pharmacological options.

Pharmacotherapies for heroin addiction may target opiate withdrawal symptoms, facilitate initiation of abstinence and/or reduce relapse to heroin use either by maintenance on an agonist or antagonist agent. Available agents include opioid agonists, partial opioid agonists, opioid antagonists and alpha 2 -agonists for use during managed withdrawal and long-term maintenance. Experimental approaches combine alpha 2 -agonists with naltrexone to reduce the time of opiate withdrawal and to accelerate the transition to abstinence. Recently, buprenorphine has been introduced in the US for office-based maintenance, with the hope of replicating the success of this treatment in Europe and Australia. Naloxone has been added to buprenorphine in order to reduce its potential diversion to intravenous use, whilst facilitating the expansion of treatment. Although comprehensive substance abuse treatment is not limited to pharmacotherapy, this review will focus on the rationale, indications and limitations of the range of existing medications for detoxification and relapse prevention treatments. The two major goals of pharmacotherapy are to relieve the severity of opiate withdrawal symptoms during the managed withdrawal of the opioid and to prevent relapse to heroin use either after abstinence initiation or after being stabilised on a long-acting opiate agonist, such as methadone.

Co-administration of opioid agonists and antagonists in addiction and pain medicine.

BACKGROUND: mu-Opioid agonists have clinically useful effects and are used in a variety of acute and chronic pain conditions. However, repeated exposure to these drugs can lead to the development of physiologic dependence and, in some individuals, to opioid addiction. OBJECTIVE: This review describes different rationales and modes of co-administration of opioid agonists and antagonists to increase and decrease the desired and undesired effects of the agonists. METHODS: Publications in the English language were identified through a MEDLINE search and the bibliographies of identified articles were reviewed. RESULTS/CONCLUSIONS: The clinical indication is a crucial determinant of how opioid agonists and antagonists are co-administered and, in turn, the selection of mode of co-administration (i.e., sequential or simultaneous) determines the most appropriate type of antagonist, dosage and route of administration. However, because each clinical application has both benefits and limitations, it is suggested that co-administration parameters need to be adjusted to the specific requirements of individual patients.