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Kratom and Pain Tolerance: A Randomized, Placebo-Controlled, Double-Blind Study

Vicknasingam B, Chooi WT, Rahim AA, Ramachandram D, Singh D, Ramanathan S, et al.

Yale J Biol Med, 2020 06;93(2):229-238.
PMID: 32607084

Background: Kratom has a long history of traditional medicine use in Southeast Asia. Consumption of kratom products has also been reported in the US and other regions of the world. Pain relief is among many self-reported kratom effects but have not been evaluated in controlled human subject research. Methods: Kratom effects on pain tolerance were assessed in a randomized, placebo-controlled, double-blind study. During a 1-day inpatient stay, participants received a randomized sequence of kratom and placebo decoctions matched for taste and appearance. Pain tolerance was measured objectively in a cold pressor task (CPT) as time (seconds) between the pain onset and the hand withdrawal from the ice bath. Health status, vital signs, objective, and subjective indicators of withdrawal symptoms, self-reported data on lifetime kratom use patterns, and assessments of blinding procedures were also evaluated. Results: Twenty-six males with the mean (SD) age 24.3 (3.4) years were enrolled. They reported the mean (SD) 6.1 (3.2) years of daily kratom consumption. Pain tolerance increased significantly 1 hour after kratom ingestion from the mean (SD) 11.2 (6.7) seconds immediately before to 24.9 (39.4) seconds 1 hour after kratom consumption (F(2,53.7)=4.33, p=0.02). Pain tolerance was unchanged after consuming placebo drinks: 15.0 (19.0) seconds immediately before and 12.0 (8.1) seconds 1 hour after consumption of placebo (F(2,52.8)=0.93, p=0.40). No discomfort or signs of withdrawal were reported or observed during 10-20 hours of kratom discontinuation. Conclusions: Kratom decoction demonstrated a substantial and statistically significant increase in pain tolerance. Further rigorous research on kratom pain-relieving properties and a safety profile is needed.

Matched MeSH terms: Analgesics/administration & dosage
Manual removal of placenta under hypoaesthesia

Menon R

Med J Malaya, 1970 Sep;25(1):17-20.
PMID: 4249487
Matched MeSH terms: Analgesics/administration & dosage
One-year Results of a Factorial Randomized Trial of Aspirin versus Placebo and Clonidine versus Placebo in Patients Having Noncardiac Surgery

Sessler DI, Conen D, Leslie K, Yusuf S, Popova E, Graham M, et al.

Anesthesiology, 2020 04;132(4):692-701.
PMID: 32022771 DOI: 10.1097/ALN.0000000000003158

BACKGROUND: The authors previously reported that perioperative aspirin and/or clonidine does not prevent a composite of death or myocardial infarction 30 days after noncardiac surgery. Moreover, aspirin increased the risk of major bleeding and clonidine caused hypotension and bradycardia. Whether these complications produce harm at 1 yr remains unknown.
METHODS: The authors randomized 10,010 patients with or at risk of atherosclerosis and scheduled for noncardiac surgery in a 1:1:1:1 ratio to clonidine/aspirin, clonidine/aspirin placebo, clonidine placebo/aspirin, or clonidine placebo/aspirin placebo. Patients started taking aspirin or placebo just before surgery; those not previously taking aspirin continued daily for 30 days, and those taking aspirin previously continued for 7 days. Patients were also randomly assigned to receive clonidine or placebo just before surgery, with the study drug continued for 72 h.
RESULTS: Neither aspirin nor clonidine had a significant effect on the primary 1-yr outcome, a composite of death or nonfatal myocardial infarction, with a 1-yr hazard ratio for aspirin of 1.00 (95% CI, 0.89 to 1.12; P = 0.948; 586 patients [11.8%] vs. 589 patients [11.8%]) and a hazard ratio for clonidine of 1.07 (95% CI, 0.96 to 1.20; P = 0.218; 608 patients [12.1%] vs. 567 patients [11.3%]), with effect on death or nonfatal infarction. Reduction in death and nonfatal myocardial infarction from aspirin in patients who previously had percutaneous coronary intervention at 30 days persisted at 1 yr. Specifically, the hazard ratio was 0.58 (95% CI, 0.35 to 0.95) in those with previous percutaneous coronary intervention and 1.03 (95% CI, 0.91to 1.16) in those without (interaction P = 0.033). There was no significant effect of either drug on death, cardiovascular complications, cancer, or chronic incisional pain at 1 yr (all P > 0.1).
CONCLUSIONS: Neither perioperative aspirin nor clonidine have significant long-term effects after noncardiac surgery. Perioperative aspirin in patients with previous percutaneous coronary intervention showed persistent benefit at 1 yr, a plausible sub-group effect.

Matched MeSH terms: Analgesics/administration & dosage*
Overcoming barriers to optimal drug dosing during ECMO in critically ill adult patients

Cheng V, Abdul-Aziz MH, Roberts JA, Shekar K

Expert Opin Drug Metab Toxicol, 2019 Feb;15(2):103-112.
PMID: 30582435 DOI: 10.1080/17425255.2019.1563596

INTRODUCTION: One major challenge to achieving optimal patient outcome in extracorporeal membrane oxygenation (ECMO) is the development of effective dosing strategies in this critically ill patient population. Suboptimal drug dosing impacts on patient outcome as patients on ECMO often require reversal of the underlying pathology with effective pharmacotherapy in order to be liberated of the life-support device. Areas covered: This article provides a concise review of the effective use of antibiotics, analgesics, and sedative by characterizing the specific changes in PK secondary to the introduction of the ECMO support. We also discuss the barriers to achieving optimal pharmacotherapy in patients on ECMO and also the current and potential research that can be undertaken to address these clinical challenges. Expert opinion: Decreased bioavailability due to sequestration of drugs in the ECMO circuit and ECMO induced PK alterations are both significant barriers to optimal drug dosing. Evidence-based drug choices may minimize sequestration in the circuit and would enable safety and efficacy to be maintained. More work to characterize ECMO related pharmacodynamic alterations such as effects of ECMO on hepatic cytochrome system are still needed. Novel techniques to increase target site concentrations should also be explored.

Matched MeSH terms: Analgesics/administration & dosage*
Fulltext Patterns of post-operative analgesic usage in adults and children

Rus-Anida A, Quah BS

Med J Malaysia, 1998 Sep;53(3):204-8.
PMID: 10968154

There appears to be a general tendency towards under-usage of analgesics not only in children but also in adults. The aim of this study was to describe the pattern of analgesic usage in adults and children admitted for major intra-abdominal surgery. All patients who had intra-abdominal surgery at University Science Malaysia Hospital (USM Hospital) from 1st January to 31st March 1995 were included in the study. Children were patients of 12 years and below and adults were patients above 12 years of age. Data including age, sex, weight, type of analgesics used, the number of patients who had analgesics ordered and administered post-operatively were obtained from the patients' medical record. A total of 48 children and 67 adults were studied. Narcotic analgesics were the most common analgesics ordered both in adults (95.5%) and in children (97%). Post-operative analgesics were ordered significantly more often for adults 67 (100%) than for children 33 (69%) (p < 0.0001). In adults, 70% of patients who had analgesics ordered post-operatively had their analgesics administered, but in children only 39.4% of patients had their analgesics administered (p < 0.001). The most common route of administration was intramuscular in both adults (95.5%) and children (88%). Analgesics were more likely to be administered in the intensive care units (100%) than in the surgical wards (60%) (p = 0.049). Elective or emergency surgery and the time of day when surgery was performed did not affect the frequency of analgesics ordered or administered. In summary, children in this hospital had less analgesics ordered and administered following intra-abdominal surgery compared to adults. The results of this study imply that increased attention should be given to relieve postoperative pain with analgesic drugs in children.

Matched MeSH terms: Analgesics/administration & dosage
Fulltext Peripheral antinociception of a chalcone, flavokawin B and possible involvement of the nitric oxide/cyclic guanosine monophosphate/potassium channels pathway

Kamaldin MN, Akhtar MN, Mohamad AS, Lajis N, Perimal EK, Akira A, et al.

Molecules, 2013 Apr 10;18(4):4209-20.
PMID: 23612473 DOI: 10.3390/molecules18044209

Previous studies have shown that systemic administration of 6'-hydroxy-2',4'-dimethoxychalcone (flavokawin B, FKB) exerts significant peripheral and central antinociceptive effects in laboratory animals. However, the mechanisms underlying these peripheral and central antinociceptive effects have yet to be elucidated. Therefore, the objective of the present study was to evaluate the participation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/potassium (K+) channels pathway in the peripheral antinociception induced by FKB. It was demonstrated that intraplantar (i.pl.) administration of FKB (150, 250, 375 and 500 µg/paw) resulted in dose-dependent peripheral antinociception against mechanical hyperalgesia in carrageenan-induced hyperalgesia test model in rats. The possibility of FKB having either a central or a systemic effect was excluded since administration of FKB into the right paw did not elicit antinociception in the contralateral paw. Furthermore, peripheral antinociception induced by FKB (500 µg/paw) was significantly reduced when L-arginine (25 µg/paw, i.pl.), Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 50 µg/paw, i.pl.), glibenclamide (300 µg/paw, i.pl.), tetraethylammonium (300 µg/paw, i.pl.) and charybdotoxin (3 µg/paw, i.pl.) were injected before treatment. Taken together, our present data suggest that FKB elicits peripheral antinociception when assessed in the mechanical hyperalgesia induced by carrageenan. In addition, it was also demonstrated that this effect was mediated through interaction of the NO/cGMP/K+ channels signaling pathway.

Matched MeSH terms: Analgesics/administration & dosage
Risk factors associated with dyspepsia in a rural Asian population and its impact on quality of life

Mahadeva S, Yadav H, Rampal S, Goh KL

Am J Gastroenterol, 2010 Apr;105(4):904-12.
PMID: 20179699 DOI: 10.1038/ajg.2010.26

The epidemiology and impact of dyspepsia in rural Asia remains uncertain. We aimed to determine the prevalence epidemiology and impact of dyspepsia in a rural Malaysian community.

Matched MeSH terms: Analgesics/administration & dosage
Fulltext Survey of postoperative pain in University Hospital Kuala Lumpur

Vijayan R, Tay KH, Tan LB, Loganathan

Singapore Med J, 1994 Oct;35(5):502-4.
PMID: 7701371

One hundred and eighty-three patients undergoing surgery were interviewed twenty-four hours following surgery to assess the quality of pain relief they received in the immediate postoperative period. Interviews were conducted using a standard questionnaire for all patients. They were asked to (1) rate the quality of pain relief they obtained on a Visual Pain Analogue Scale (VPAS-0 being no pain and 10 being the worst imaginable pain); (2) state whether they were happy and satisfied with the pain relief they received; (3) if dissatisfied, they were asked to give their reasons. 37.7% (69 patients) had moderate to severe pain--pain score greater than 6 on the VPAS. Most of these patients had undergone abdominal or major orthopaedic surgery. 32.7% (60 patients) were unhappy with their postoperative pain control. The main reasons for complaint from the patients were that analgesic injections were either not given promptly or were not given at all. The survey also highlighted the inadequate under-administration of narcotic injections in the postoperative period despite orders being written up. It showed there is an urgent need for setting up an Acute Pain Service for better postoperative pain control. An anaesthesiology based Acute Pain Service was started in October 1992.

Matched MeSH terms: Analgesics/administration & dosage
Fulltext Topical piroxicam in vitro release and in vivo anti-inflammatory and analgesic effects from palm oil esters-based nanocream

Abdulkarim MF, Abdullah GZ, Chitneni M, Salman IM, Ameer OZ, Yam MF, et al.

Int J Nanomedicine, 2010 Nov 04;5:915-24.
PMID: 21116332 DOI: 10.2147/IJN.S13305

INTRODUCTION: During recent years, there has been growing interest in use of topical vehicle systems to assist in drug permeation through the skin. Drugs of interest are usually those that are problematic when given orally, such as piroxicam, a highly effective anti-inflammatory, anti-pyretic, and analgesic, but with the adverse effect of causing gastrointestinal ulcers. The present study investigated the in vitro and in vivo pharmacodynamic activity of a newly synthesized palm oil esters (POEs)-based nanocream containing piroxicam for topical delivery.
METHODS: A ratio of 25:37:38 of POEs: external phase: surfactants (Tween 80:Span 20, in a ratio 80:20), respectively was selected as the basic composition for the production of a nanocream with ideal properties. Various nanocreams were prepared using phosphate-buffered saline as the external phase at three different pH values. The abilities of these formulae to deliver piroxicam were assessed in vitro using a Franz diffusion cell fitted with a cellulose acetate membrane and full thickness rat skin. These formulae were also evaluated in vivo by comparing their anti-inflammatory and analgesic activities with those of the currently marketed gel.
RESULTS: After eight hours, nearly 100% of drug was transferred through the artificial membrane from the prepared formula F3 (phosphate-buffered saline at pH 7.4 as the external phase) and the marketed gel. The steady-state flux through rat skin of all formulae tested was higher than that of the marketed gel. Pharmacodynamically, nanocream formula F3 exhibited the highest anti- inflammatory and analgesic effects as compared with the other formulae.
CONCLUSION: The nanocream containing the newly synthesized POEs was successful for trans-dermal delivery of piroxicam.

Matched MeSH terms: Analgesics/administration & dosage*
Fulltext Zerumbone Alleviates Neuropathic Pain through the Involvement of l-Arginine-Nitric Oxide-cGMP-K⁺ ATP Channel Pathways in Chronic Constriction Injury in Mice Model

Zulazmi NA, Gopalsamy B, Min JC, Farouk AA, Sulaiman MR, Bharatham BH, et al.

Molecules, 2017 Mar 30;22(4).
PMID: 28358309 DOI: 10.3390/molecules22040555

The present study investigates the involvement of the l-arginine-Nitric Oxide-cGMP-K⁺ ATP pathways responsible for the action of anti-allodynic and antihyperalgesic activities of zerumbone in chronic constriction injury (CCI) induced neuropathic pain in mice. The role of l-arginine-NO-cGMP-K⁺ was assessed by the von Frey and the Randall-Selitto tests. Both allodynia and hyperalgesia assessments were carried out on the 14th day post CCI, 30 min after treatments were given for each respective pathway. Anti-allodynic and antihyperalgesic effects of zerumbone (10 mg/kg, i.p) were significantly reversed by the pre-treatment of l-arginine (10 mg/kg), 1H [1,2,4]Oxadiazole[4,3a]quinoxalin-1-one (ODQ), a soluble guanosyl cyclase blocker (2 mg/kg i.p.) and glibenclamide (ATP-sensitive potassium channel blocker) (10 mg/kg i.p.) (p < 0.05). Taken together, these results indicate that systemic administration of zerumbone produces significant anti-allodynic and antihyperalgesic activities in neuropathic pain in mice possibly due to involvement of the l-arginine-NO-cGMP-PKG-K⁺ ATP channel pathways in CCI model.

Matched MeSH terms: Analgesics/administration & dosage*