Proposed multidimensional pain outcome methodology to demonstrate analgesic drug efficacy and facilitate future drug approval for piglet castration

Castration of male piglets in the United States is conducted without analgesics because no Food and Drug Administration (FDA) approved products are labeled for pain control in swine. The absence of approved products is primarily due to a wide variation in how pain is measured in suckling piglets and the lack of validated pain-specific outcomes individually indistinct from other biological responses, such as general stress or inflammation responses with cortisol. Simply put, to measure pain mitigation, measurement of pain must be specific, quantifiable, and defined. Therefore, given the need for mitigating castration pain, a consortium of researchers, veterinarians, industry, and regulatory agencies was formed to identify potential animal-based outcomes and develop a methodology, based on the known scientific research, to measure pain and the efficacy of mitigation strategies. The outcome-based measures included physiological, neuroendocrine, behavioral, and production parameters. Ultimately, this consortium aims to provide a validated multimodal methodology to demonstrate analgesic drug efficacy for piglet castration. Measurable outcomes were selected based on published studies suggesting their validity, reliability, and sensitivity for the direct or indirect measurement of pain associated with surgical castration in piglets. Outcomes to be considered are observation of pain behaviors (i.e. ethogram defined behaviors and piglet grimace scale), gait parameters measured with a pressure mat, infrared thermography of skin temperature of the cranium and periphery of the eye, and blood biomarkers. Other measures include body weight and mortality rate. This standardized measurement of the outcome variable's primary goal is to facilitate consistency and rigor by developing a research methodology utilizing endpoints that are well-defined and reliably measure pain in piglets. The resulting methodology will facilitate and guide the evaluation of the effectiveness of comprehensive analgesic interventions for 3- to 5-day-old piglets following surgical castration.

The effect of transcutaneous electrical nerve stimulation (TENS) on pain control and phenylethanolamine-N-methyltransferase (PNMT) gene expression after cesarean section

Transcutaneous electrical nerve stimulation (TENS) is one of the non-pharmacological methods of pain relief that has been able to reduce pain by 70 to 90% in postoperative pain control. This study aimed to determine the effect of TENS on pain control after cesarean section and its effect on PNMT gene expression. For this purpose, a double-blind randomized clinical trial was performed on 70 Chinese patients with elective cesarean section. Patients were divided into case and control groups. In the case group, TENS and analgesic drugs were used to relieve pain, and in the control group, the only analgesic drug was used. Then the severity of pain, recurrence of pain attacks, the number of analgesic drugs used and the amount of analgesic drug used in the first 24 hours after surgery were evaluated and compared. Blood samples were also taken from patients to evaluate PNMT gene expression. The semi-quantitative RT-PCR was used to study changes in gene expression. The results showed that the group treated with TENS had less pain intensity and less recurrence of pain attacks than the group that received only analgesic medication. Also, the frequency of analgesic drug use and its dose in the TENS group were significantly lower than in the control group. TENS, on the other hand, has been able to greatly reduce the expression of the PNMT gene, which is produced during times of stress. Therefore, it is recommended that TENS be used as a non-invasive and non-pharmacological adjuvant effective in reducing pain after cesarean section.

Genome Mining-Based Discovery of Blenny Fish-Derived Peptides Targeting the Mouse κ-Opioid Receptor

Over the past years, peptides have attracted increasing interest for G protein-coupled receptor (GPCR) drug discovery and development. Peptides occupy a unique chemical space that is not easily accessible for small molecules and antibodies and provide advantages over these ligand classes such as lower toxicity and higher selectivity. The κ-opioid receptor (KOR) is a prototypic GPCR and an appealing therapeutic target for the development of safer and more effective analgesics. Recently, peptides have emerged as analgesic drug candidates with improved side effect profiles. We have previously identified plant-derived peptides, which activate KOR. Based on this precedent, here we relied on publicly available databases to discover novel KOR peptide ligands by genome mining. Using human preprodynorphin as a query, we identified blenny fish-derived peptides, referred to as blenniorphins, capable of binding to and activating KOR with nanomolar affinity and potency, respectively. Additionally, the blenniorphins altered β-arrestin-2 recruitment at the KOR. Our study demonstrates the utility of genome mining to identify peptide GPCR ligands with intriguing pharmacological properties and unveils the potential of blenny fishes as a source for novel KOR ligands.

Methodology and applicability of the human contact burn injury model: A systematic review

The contact burn injury model is an experimental contact thermode-based physiological pain model primarily applied in research of drug efficacy in humans. The employment of the contact burn injury model across studies has been inconsistent regarding essential methodological variables, challenging the validity of the model. This systematic review analyzes methodologies, outcomes, and research applications of the contact burn injury model. Based on these results, we propose an improved contact burn injury testing paradigm. A literature search was conducted (15-JUL-2020) using PubMed, EMBASE, Web of Science, and Google Scholar. Sixty-four studies were included. The contact burn injury model induced consistent levels of primary and secondary hyperalgesia. However, the analyses revealed variations in the methodology of the contact burn injury heating paradigm and the post-burn application of test stimuli. The contact burn injury model had limited testing sensitivity in demonstrating analgesic efficacy. There was a weak correlation between experimental and clinical pain intensity variables. The data analysis was limited by the methodological heterogenicity of the different studies and a high risk of bias across the studies. In conclusion, although the contact burn injury model provides robust hyperalgesia, it has limited efficacy in testing analgesic drug response. Recommendations for future use of the model are being provided, but further research is needed to improve the sensitivity of the contact burn injury method. The protocol for this review has been published in PROSPERO (ID: CRD42019133734).

Acupuncture Combined with Three-Step Analgesic Drug Therapy for Treatment of Cancer Pain: A Systematic Review and Meta-Analysis of Randomised Clinical Trials

Objective. The purpose of this study was to systematically evaluate the efficacy and safety of acupuncture combined with the WHO three-step analgesic drug ladder for cancer pain. Methods. The Cochrane Library, PubMed, and CNKI Database of Systematic Reviews were searched. Using the Cochrane Register for Randomized Controlled Trials, the quality of the included literature was evaluated, and the meta-analysis was carried out with RevMan 5.3 software. Results. Compared with three-step analgesia alone, acupuncture combined with three-step analgesia for cancer pain increased pain relief response rates (RR = 1.12, 95% CI: 1.08∼1.17, P < 0.00001 ), reduced NRS score (SMD = −1.10, 95% CI: −1.86∼−0.35, P = 0.004 ), reduced the rate of side effects (RR = 0.45, 95% CI: 0.38∼0.53, P < 0.00001 ), including nausea ( P < 0.00001 ), vomiting ( P = 0.008 ), constipation ( P < 0.00001 ), and dizziness ( P = 0.010 ), reduced the burst pain rate (SMD = −1.38; 95% CI: −2.44∼−0.32, P = 0.01 ), shortened analgesia effect onset time ( P = 0.004 ), and extended the duration of response ( P < 0.0001 ). Conclusion. For the treatment of cancer pain, acupuncture combined with three-step analgesic drugs is better than using only three-step analgesic drugs.

Assessing the Knowledge of Analgesic Drugs Utilization during Pregnancy among Women in Saudi Arabia: A Cross-Sectional Study

Background: Pain is a common compensation mechanism in pregnant women that they may face during gestation due to physiological changes. Paracetamol and non-steroidal anti-inflammatory drugs are the most administered analgesic drugs worldwide. Therefore, safety and efficacy are important measures for the use of analgesics during pregnancy. Objective: Assess the knowledge of analgesic drug utilization among Saudi pregnant women. Method: We conducted a self-administered survey with an electronic questionnaire via Google Drive among a sample of 406 Saudi women. Results: About half of the respondents took analgesics during the first trimester, and 52.5% of women have used analgesics at least once without any medical advice during their gestation. Most participants agreed that paracetamol is the safest and effective analgesic drug during pregnancy, yet 61.8% of women are not aware that analgesics could be detrimental to the fetus if inappropriately administered in the third trimester. Conclusion: Participants have a good perception of the safest and most effective analgesic drug during pregnancy, but they have poor knowledge about analgesics’ side effects.