The Contribution of Nitroxidative Stress to Pathophysiological Pain and Opioid Analgesic Failure

Background: Pain-relief prescriptions have led to an alarming increase in drug-related abuse. Objective: In this study, we estimate the pain reliever prescription rates at a major German academic hospital center and compare with the nationwide trends from Germany and prescription reports from the USA. Methods: We analysed >500,000 discharge summaries from Charité, encompassing the years 2006 to 2015, and extracted the medications and diagnoses from each discharge summary. Prescription reports from the USA and Germany were collected and compared with the trends at Charité to identify the frequently prescribed pain relievers and their world-wide utilization trends. The average costs of pain therapy were also calculated and compared between the three regions. Results: Metamizole (dipyrone), a non-opioid analgesic, was the most commonly prescribed pain reliever at Charité (59%) and in Germany (23%) while oxycodone (29%), a semi-synthetic opioid, was most commonly ordered in the USA. Surprisingly, metamizole was prescribed to nearly 20% of all patients at Charité, a drug that has been banned for safety reasons (agranulocytosis) in most developed countries including Canada, United Kingdom, and USA. A large number of prospective cases with high risk for agranulocytosis and other side effects were found. The average cost of pain therapy greatly varied between the USA (125.3 EUR) and Charité (17.2 EUR). Conclusion: The choice of pain relievers varies regionally and is often in disagreement with approved indications and regulatory guidelines. A pronounced East-West gradient was observed with metamizole use and the opposite with prescription opioids.

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

Current Psychopharmacologye ◽

10.2174/2211556009999200628093231 ◽

2020 ◽

Vol 9 (3) ◽

pp. 164-184

Author(s):

Raymond Brewer ◽

Kenneth Blum ◽

Abdalla Bowirrat ◽

Edward J. Modestino ◽

David Baron ◽

...

Keyword(s):

Opioid Analgesic ◽

Opioid Analgesics ◽

Well Being ◽

Deficiency Syndrome ◽

Pain Tolerance ◽

Opioid Agonist ◽

Opioid Agonist Therapy ◽

Analgesic Agents ◽

Opioid Induced Hyperalgesia ◽

Intensive Investigation

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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Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling

Biomolecules ◽

10.3390/biom11060864 ◽

2021 ◽

Vol 11 (6) ◽

pp. 864

Author(s):

Christopher L. Cioffi

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Therapeutic Potential ◽

Opioid Analgesic ◽

Critical Role ◽

Analgesic Efficacy ◽

Standard Of Care ◽

Current Standard ◽

Glycine Transporters ◽

Pathological Pain

Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal cord in inflammatory and neuropathic pain models and is a key maladaptive mechanism causing mechanical hyperalgesia and allodynia. Thus, it has been hypothesized that pharmacological agents capable of augmenting glycinergic tone within the dorsal horn may be able to blunt or block aberrant nociceptor signaling to the brain and serve as a novel class of analgesics for various pathological pain states. Indeed, drugs that enhance dysfunctional glycinergic transmission, and in particular inhibitors of the glycine transporters (GlyT1 and GlyT2), are generating widespread interest as a potential class of novel analgesics. The GlyTs are Na+/Cl−-dependent transporters of the solute carrier 6 (SLC6) family and it has been proposed that the inhibition of them presents a possible mechanism by which to increase spinal extracellular glycine concentrations and enhance GlyR-mediated inhibitory neurotransmission in the dorsal horn. Various inhibitors of both GlyT1 and GlyT2 have demonstrated broad analgesic efficacy in several preclinical models of acute and chronic pain, providing promise for the approach to deliver a first-in-class non-opioid analgesic with a mechanism of action differentiated from current standard of care. This review will highlight the therapeutic potential of GlyT inhibitors as a novel class of analgesics, present recent advances reported for the field, and discuss the key challenges associated with the development of a GlyT inhibitor into a safe and effective agent to treat pain.

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Participants with mild, moderate, or severe pain following total hip arthroplasty. A sub-study of the PANSAID trial on paracetamol and ibuprofen for postoperative pain treatment

Scandinavian Journal of Pain ◽

10.1515/sjpain-2020-0141 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Luma Mahmoud Issa ◽

Kasper Højgaard Thybo ◽

Daniel Hägi-Pedersen ◽

Jørn Wetterslev ◽

Janus Christian Jakobsen ◽

...

Keyword(s):

Postoperative Pain ◽

Total Hip Arthroplasty ◽

Hip Arthroplasty ◽

Severe Pain ◽

Pain Treatment ◽

Opioid Analgesic ◽

Opioid Use ◽

Mild Pain ◽

Total Hip ◽

Pain Scores

AbstractObjectivesIn this sub-study of the ‘Paracetamol and Ibuprofen in Combination’ (PANSAID) trial, in which participants were randomised to one of four different non-opioids analgesic regimen consisting of paracetamol, ibuprofen, or a combination of the two after planned primary total hip arthroplasty, our aims were to investigate the distribution of participants’ pain (mild, moderate or severe), integrate opioid use and pain to a single score (Silverman Integrated Approach (SIA)-score), and identify preoperative risk factors for severe pain.MethodsWe calculated the proportions of participants with mild (VAS 0–30 mm), moderate (VAS 31–60 mm) or severe (VAS 61–100 mm) pain and the SIA-scores (a sum of rank-based percentage differences from the mean rank in pain scores and opioid use, ranging from −200 to 200%). Using logistic regression with backwards elimination, we investigated the association between severe pain and easily obtainable preoperative patient characteristics.ResultsAmong 556 participants from the modified intention-to-treat population, 33% (95% CI: 26–42) (Group Paracetamol + Ibuprofen (PCM + IBU)), 28% (95% CI: 21–37) (Group Paracetamol (PCM)), 23% (95% CI: 17–31) (Group Ibuprofen (IBU)), and 19% (95% CI: 13–27) (Group Half Strength-Paracetamol + Ibuprofen (HS-PCM + IBU)) experienced mild pain 6 h postoperatively during mobilisation. Median SIA-scores during mobilisation were: Group PCM + IBU: −48% (IQR: −112 to 31), Group PCM: 40% (IQR: −31 to 97), Group IBU: −5% (IQR: −57 to 67), and Group HS-PCM + IBU: 6% (IQR: −70 to 74) (overall difference: p=0.0001). Use of analgesics before surgery was the only covariate associated with severe pain (non-opioid: OR 0.50, 95% CI: 0.29–0.82, weak opioid 0.56, 95% CI: 0.28–1.16, reference no analgesics before surgery, p=0.02).ConclusionsOnly one third of participants using paracetamol and ibuprofen experienced mild pain after total hip arthroplasty and even fewer experienced mild pain using each drug alone as basic non-opioid analgesic treatment. We were not able, in any clinically relevant way, to predict severe postoperative pain. A more extensive postoperative pain regimen than paracetamol, ibuprofen and opioids may be needed for a large proportion of patients having total hip arthroplasty. SIA-scores integrate pain scores and opioid use for the individual patient and may add valuable information in acute pain research.

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