Transmodulation of Dopaminergic Signaling to Mitigate Hypodopminergia and Pharmaceutical Opioid-induced Hyperalgesia

Neuroscientists and psychiatrists working in the areas of “pain and addiction” are asked in this perspective article to reconsider the current use of dopaminergic blockade (like chronic opioid agonist therapy), and instead to consider induction of dopamine homeostasis by putative pro-dopamine regulation. Pro-dopamine regulation could help pharmaceutical opioid analgesic agents to mitigate hypodopaminergia-induced hyperalgesia by inducing transmodulation of dopaminergic signaling. An optimistic view is that early predisposition to diagnosis based on genetic testing, (pharmacogenetic/pharmacogenomic monitoring), combined with appropriate urine drug screening, and treatment with pro-dopamine regulators, could conceivably reduce stress, craving, relapse, enhance well-being and attenuate unwanted hyperalgesia. These concepts require intensive investigation. However, based on the rationale provided herein, there is a good chance that combining opioid analgesics with genetically directed pro-dopamine-regulation using KB220 (supported by 43 clinical studies). This prodopamine regulator may become a front-line technology with the potential to overcome, in part, the current heightened rates of chronic opioid-induced hyperalgesia and concomitant Reward Deficiency Syndrome (RDS) behaviors. Current research does support the hypothesis that low or hypodopaminergic function in the brain may predispose individuals to low pain tolerance or hyperalgesia.

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Designing Opioids That Deter Abuse

Pain Research and Treatment ◽

10.1155/2012/282981 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Robert B. Raffa ◽

Joseph V. Pergolizzi ◽

Edmundo Muñiz ◽

Robert Taylor ◽

Jason Pergolizzi

Keyword(s):

Current Knowledge ◽

Opioid Analgesic ◽

Opioid Abuse ◽

Prescription Opioid ◽

Opioid Agonist ◽

Biological Targets ◽

Actual Use ◽

Analgesic Agents ◽

Physical Barriers ◽

Public Health Challenge

Prescription opioid formulations designed to resist or deter abuse are an important step in reducing opioid abuse. In creating these new formulations, the paradigm of drug development target should be introduced. Biological targets relating to the nature of addiction may pose insurmountable hurdles based on our current knowledge and technology, but products that use behavioral targets seem logical and feasible. The population of opioid abusers is large and diverse so behavioral targets are more challenging than they appear at first glance. Furthermore, we need to find ways to correlate behavioral observations of drug liking to actual use and abuse patterns. This may involve revisiting some pharmacodynamic concepts in light of drug effect rather than peak concentration. In this paper we present several new opioid analgesic agents designed to resist or deter abuse using physical barriers, the inclusion of an opioid agonist or antagonist, an aversive agent, and a prodrug formulation. Further, this paper also provides insight into the challenges facing drug discovery in this field. Designing and screening for opioids intended to resist or deter abuse is an important step to meet the public health challenge of burgeoning prescription opioid abuse.

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Combination Opioid Analgesics

January 2018 - Pain Physician ◽

10.36076/ppj.2008/11/201 ◽

2008 ◽

Vol 2;11 (3;2) ◽

pp. 201-214

Author(s):

Howard Smith

Keyword(s):

Adverse Effects ◽

Opioid Analgesic ◽

Analgesic Efficacy ◽

Opioid Analgesics ◽

Active Metabolites ◽

Analgesic Tolerance ◽

Key Words Pain ◽

Long Duration ◽

Wide Range ◽

Opioid Induced Hyperalgesia

Although there is no “ideal analgesic,” scientists and clinicians alike continue to search for compounds with qualities which may approach the “ideal analgesic.” Characteristics of an “ideal” analgesic may include: the agent is a full agonist providing optimal/maximal analgesia for a wide range/variety of pain states (e.g., broad spectrum analgesic activity), it does not exhibit tolerance, it produces no unwanted effects and minimal adverse effects, it has no addictive potential, it does not facilitate pain/hyperalgesia, it has a long duration, it has high oral bioavailability, it is not vulnerable to important drug interactions, it is not significantly bound to plasma proteins, it has no active metabolites, it has linear kinetics, and it is eliminated partly by hydrolysis to an inactive metabolite (without involvement of oxidative and conjugative enzymes). Investigators have concentrated on ways to alter existing analgesics or to combine existing analgesic compounds with compounds which may improve efficacy over time or minimize adverse effects. The addition of an analgesic with a second agent (which may or may not also be an analgesic) to achieve a “combination analgesic” is a concept which has been exploited for many years. Although there may be many reasons to add 2 agents together in efforts to achieve analgesia, for purposes of this article — reasons for combining an opioid with a second agent to produce a combination opioid analgesic may be classified into 6 major categories: 1.) combinations to prolong analgesic duration; 2.) combinations to enhance or optimize analgesic efficacy (e.g., analgesic synergy); 3.) combinations to diminish or minimize adverse effects; 4.) combinations to diminish opioid effects which are not beneficial (or contrariwise to or enhance beneficial opioid effects); 5.) combinations to reduce opioid tolerance/opioid-induced hyperalgesia; and 6.) combinations to combat dependency issues/addiction potential/craving sensations. Combination opioid analgesics are one avenue which may give rise to “pain pills” with improved analgesic profiles over existing analgesic medications. Key words: Pain, combination opioid analgesic, tolerance, opioid-induced hyperalgesia

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Analgesics in anaesthetic practice

10.1093/med/9780199642045.003.0018 ◽

2017 ◽

Author(s):

John Williams ◽

Francis Bonnet

Keyword(s):

Postoperative Pain ◽

Opioid Analgesic ◽

Postoperative Outcome ◽

Perioperative Period ◽

Well Being ◽

Number Needed To Treat ◽

Analgesic Agents ◽

The Central Nervous System ◽

Sensory Consequence ◽

History Of Use

Each year, approximately 230 million major surgical procedures are undertaken worldwide, with over three-quarters of the patients complaining of pain postoperatively and 10% complaining of severe pain. Pain is not, however, just an unpleasant sensory consequence of surgery, but can also have significant physiological implications impacting negatively on well-being and postoperative outcome. Postoperative pain may also result in changes within the central nervous system, leading to the development of chronic pain states lasting in excess of 3–6 months. Adequate analgesia has proven to be effective when employed in the perioperative period at combating many of these adverse effects. An understanding of the basic physiological and pharmacological mechanisms responsible for producing, transmitting, and sustaining pain has allowed for a variety of effective analgesic agents to be fashioned and used clinically to treat pain. Morphine, the archetypal opioid analgesic, is the most familiar of these agents with a long history of use and evidence of effectiveness; morphine possesses a number-needed-to-treat (NNT) to reduce pain by 50% of around 3 when given in doses of between 10 and 15 mg. Non-steroidal agents and paracetamol are similarly effective in the immediate postoperative period with NNTs of between 2 and 4. More recently, a number of analgesic adjuncts such as gabapentin, pregabalin, ketamine, clonidine, and nefopam have found favour for the treatment of acute postoperative pain. None of these agents, however, are without side-effects, ensuring that the search for effective analgesic agents continues to be a vibrant area of research with new analgesic agents continuing to be developed.

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Pain-facilitating medullary neurons contribute to opioid-induced respiratory depression

Journal of Neurophysiology ◽

10.1152/jn.00563.2012 ◽

2012 ◽

Vol 108 (9) ◽

pp. 2393-2404 ◽

Cited By ~ 25

Author(s):

Ryan S. Phillips ◽

Daniel R. Cleary ◽

Julia W. Nalwalk ◽

Seksiri Arttamangkul ◽

Lindsay B. Hough ◽

...

Keyword(s):

Respiratory Depression ◽

Opioid Analgesic ◽

Opioid Analgesics ◽

Opioid Peptide ◽

Pain Modulation ◽

Opioid Antagonist ◽

Opioid Agonist ◽

Ventromedial Medulla ◽

Cell Firing ◽

Opposing Effects

Respiratory depression is a therapy-limiting side effect of opioid analgesics, yet our understanding of the brain circuits mediating this potentially lethal outcome remains incomplete. Here we studied the contribution of the rostral ventromedial medulla (RVM), a region long implicated in pain modulation and homeostatic regulation, to opioid-induced respiratory depression. Microinjection of the μ-opioid agonist DAMGO in the RVM of lightly anesthetized rats produced both analgesia and respiratory depression, showing that neurons in this region can modulate breathing. Blocking opioid action in the RVM by microinjecting the opioid antagonist naltrexone reversed the analgesic and respiratory effects of systemically administered morphine, showing that this region plays a role in both the analgesic and respiratory-depressant properties of systemically administered morphine. The distribution of neurons directly inhibited by RVM opioid microinjection was determined with a fluorescent opioid peptide, dermorphin-Alexa 594, and found to be concentrated in and around the RVM. The non-opioid analgesic improgan, like DAMGO, produced antinociception but, unlike DAMGO, stimulated breathing when microinjected into the RVM. Concurrent recording of RVM neurons during improgan microinjection showed that this agent activated RVM ON-cells, OFF-cells, and NEUTRAL-cells. Since opioids are known to activate OFF-cells but suppress ON-cell firing, the differential respiratory response to these two analgesic drugs is best explained by their opposing effects on the activity of RVM ON-cells. These findings show that pain relief can be separated pharmacologically from respiratory depression and identify RVM OFF-cells as important central targets for continued development of potent analgesics with fewer side effects.

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