Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Pain. 2024 Oct 29. doi: 10.1097/j.pain.0000000000003446. Online ahead of
print.

Comparative risk of mortality in new users of prescription opioids for noncancer 
pain: results from the International Pharmacosurveillance Study.

Jani M(1)(2)(3), Girard N(4)(5), Bates DW(6)(7)(8), Buckeridge DL(4)(5), Dixon 
WG(1)(2)(3), Tamblyn R(4)(5).

Author information:
(1)Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal 
Research. The University of Manchester, UK.
(2)Department of Rheumatology, Salford Royal Foundation Trust, Salford, United 
Kingdom.
(3)NIHR Manchester Biomedical Research Centre, Manchester University NHS 
Foundation Trust, Manchester Academic Health Science Centre, Manchester, United 
Kingdom.
(4)Department of Epidemiology, Biostatistics, and Occupational Health, 
University of McGill, Montreal, QC, Canada.
(5)Clinical and Health Informatics Research Group, McGill University, Montreal, 
QC, Canada.
(6)Harvard Medical School, Boston, MA, United States.
(7)Division of General Internal Medicine, Brigham and Women's Hospital, Boston, 
MA, United States.
(8)Department of Health Policy and Management, Harvard T.H. Chan School of 
Public Health, Boston, MA, United States.

Although opioids continue to be used internationally for noncancer pain, 
evidence to date on the comparative safety of different opioids is sparse and 
conflicting. The aim of this study was to examine the comparative risk of 
all-cause mortality in patients newly initiated on opioids for noncancer pain, 
across 3 jurisdictions in the United Kingdom (UK), United States, and Canada. A 
multicentre retrospective, population-based cohort study was conducted. Data 
sources included UK national primary care electronic health records (Clinical 
Practice Research Datalink), The Partners HealthCare Research Patient Data in 
Boston (US), and The Montreal Population Health Record data (Canada). New users 
of opioids aged ≥18 years without cancer were included. Patients with a 
diagnosis of a pain condition and with known back pain were analysed separately. 
Fully adjusted hazard ratios (HRs) were calculated using Cox-proportional models 
and adjusted for confounders. In total, 1,066,216 patients were included (UK: n 
= 993,294; Boston, US: n = 43,243; Montreal, Canada: n = 26,116). Compared with 
codeine, patients using morphine had a significantly higher adjusted risk in the 
UK {HR: 12.58 [95% confidence interval (CI), 11.87-13.32]}, US (HR: 8.62 [95% 
CI, 3.34-22.27]), and Canadian cohorts (HR: 6.69; [95% CI, 1.35-32.22]). In 
addition, other factors associated with higher mortality were being on 
combination opioids, fentanyl, buprenorphine, and oxycodone. Compared with those 
on <50 morphine milligram equivalents/day, patients on higher-doses experience 
an incremental increase in risk. In new users of opioids, compared with codeine, 
strong opioids, including morphine, fentanyl, buprenorphine, oxycodone, and 
combination opioids, and those on ≥50 morphine milligram equivalent/day were 
associated with a higher subsequent risk of all-cause mortality.

Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on 
behalf of the International Association for the Study of Pain.

DOI: 10.1097/j.pain.0000000000003446
PMID: 39503752


2. Mikrochim Acta. 2024 Nov 4;191(12):722. doi: 10.1007/s00604-024-06787-2.

Graphene quantum dots modified electrodes as electrochemical sensing tool 
towards the detection of codeine in biological fluids and soft drinks.

Ferrer-Biechy L(1), Soriano ML(2), Lucena R(1), Cárdenas S(3).

Author information:
(1)Affordable and Sustainable Sample Preparation (AS₂P) Research Group, 
Analytical Chemistry Departament, Instituto Químico para la Energía y el 
Medioambiente (IQUEMA), Universidad de Córdoba, Campus de Rabanales, Marie Curie 
building, E-14071, Córdoba, Spain.
(2)Affordable and Sustainable Sample Preparation (AS₂P) Research Group, 
Analytical Chemistry Departament, Instituto Químico para la Energía y el 
Medioambiente (IQUEMA), Universidad de Córdoba, Campus de Rabanales, Marie Curie 
building, E-14071, Córdoba, Spain. laura.soriano@uco.es.
(3)Affordable and Sustainable Sample Preparation (AS₂P) Research Group, 
Analytical Chemistry Departament, Instituto Químico para la Energía y el 
Medioambiente (IQUEMA), Universidad de Córdoba, Campus de Rabanales, Marie Curie 
building, E-14071, Córdoba, Spain. qa1caarm@uco.es.

An electroanalytical method based on disposable screen-printed carbon electrodes 
modified with non-toxic carbonaceous nanodots is proposed as a reliable and 
effective device for codeine determination in biological fluids and soft drinks. 
Graphene quantum dots (GQDs), carbon quantum dots (CQDs) and carbon nanodots 
(CNDs) were evaluated as electrode modifiers for the determination of the drug. 
The electroactive areas of the modified electrodes were assessed by cyclic 
voltammetry using potassium ferricyanide. Results demonstrated that GQDs 
provided the best analytical response for codeine, displaying an intense and 
well-defined anodic wave approximately 0.9 V vs reference electrode. The method 
exhibits an acceptable linear dynamic range, low limits of detection and 
quantification (0.21 and 0.73 µM, respectively), and satisfactory precision 
(below 3.9% expressed as relative standard deviation (RSD)) in saliva. Only the 
analysis of biofluids requires a simple extraction protocol. The feasibility and 
applicability of this novel approach were assessed by determining codeine in 
different matrices, with recoveries ranging from 69 to 112%. This 
cost-effective, simple, easily miniaturised and portable method was applied not 
only to biofluids but also for the direct detection of codeine in soft drinks 
combined with a codeine-enriched syrup, a medication that is being used to 
adulterate beverages, particularly at specific events (drinking and nightclub 
parties). There is no need for any sample treatment, demonstrating its 
versatility in analysing beverages for potential adulteration as well.

© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, 
part of Springer Nature.

DOI: 10.1007/s00604-024-06787-2
PMID: 39489812 [Indexed for MEDLINE]


3. Front Pharmacol. 2024 Oct 14;15:1408024. doi: 10.3389/fphar.2024.1408024. 
eCollection 2024.

Community pharmacists' role towards preventing abuse or misuse and dependence of 
codeine-containing analgesic medications in Saudi Arabia: a multicenter 
cross-sectional study.

Alanazi M(#)(1), Ansari M(#)(1), Alharby TN(#)(1).

Author information:
(1)Department of Clinical Pharmacy, College of Pharmacy, University of Hail, 
Hail, Saudi Arabia.
(#)Contributed equally

INTRODUCTION: The misuse or abuse and dependence of medications containing 
codeine continue to be a major global public health concern. This study aimed to 
investigate the role of community pharmacists in preventing the abuse or misuse 
and dependence of codeine-containing analgesic drugs in Saudi Arabia.
METHODS: A cross-sectional study involving 226 community pharmacists from 
various community pharmacies across multiple cities of Saudi Arabia was 
conducted from 09 May 2023 to 09 October 2023. Study data were collected and 
managed using Research Electronic Data Capture tool. Fourteen trained data 
collectors visited randomly selected community pharmacies in different cities, 
provided pharmacists with an electronic questionnaire link, and collected their 
responses electronically. The dataset was downloaded in SPSS format, and 
analyzed for both descriptive and inferential purposes.
RESULTS: The primary indicators that community pharmacists considered when 
suspecting cases of abuse or misuse and dependence included customers who 
requested a larger quantity of the medication (88.5%), frequently visited the 
pharmacy and sought the specific medicine (82.7%), and those who took advantage 
of the crowd (70.8%). Pharmacists have been instrumental in preventing abuse or 
misuse and dependence by ensuring that medicines with abuse potential are not 
easily accessible to consumers (87.6%), providing alternative options (81%), 
reducing the dose (65%), referring patients to physicians (62.4%), and refusing 
to sell or denying availability (54.9%). Additionally, pharmacists primarily 
focused on raising public awareness (85%) as a noteworthy proportion of 
customers (54.9%) became desperate to obtain the drug after missing a dose. It 
was also suggested that community pharmacists should receive specialized 
training in substance abuse or misuse, as 46.9% of them lacked such training.
DISCUSSION: Community pharmacists, being frequently the initial point of contact 
easily reachable, possess the capability to greatly assist in identifying the 
patients and averting abuse or misuse and dependence during the dispensing of 
medication. Further, they can provide valuable guidance to those involved in 
efforts to reduce drug abuse or misuse and dependence.

Copyright © 2024 Alanazi, Ansari and Alharby.

DOI: 10.3389/fphar.2024.1408024
PMCID: PMC11513330
PMID: 39469620

Conflict of interest statement: The authors declare that the research was 
conducted in the absence of any commercial or financial relationships that could 
be construed as a potential conflict of interest.


4. Drugs Aging. 2024 Oct 27. doi: 10.1007/s40266-024-01151-8. Online ahead of 
print.

Pharmacological Pain Treatment in Older Persons.

Pickering G(1), Kotlińska-Lemieszek A(2), Krcevski Skvarc N(3), O'Mahony 
D(4)(5), Monacelli F(6), Knaggs R(7)(8)(9), Morel V(10), Kocot-Kępska M(11).

Author information:
(1)Clinical Pharmacology Department, PIC/CIC Inserm 1405-University Hospital CHU 
and Faculty of Medicine, Université Clermont Auvergne, Clermont-Ferrand, France. 
gisele.pickering@uca.fr.
(2)Department of Palliative Medicine, Pharmacotherapy in Palliative Care 
Laboratory, Poznan University of Medical Sciences, Poznań, Poland.
(3)Institute for Palliative Medicine and Care, Faculty of Medicine of University 
Maribor, Maribor, Slovenia.
(4)Department of Medicine, University College Cork, Cork University Hospital, 
Cork, Ireland.
(5)Department of Geriatric and Stroke Medicine, Cork University Hospital, Cork, 
Ireland.
(6)DIMI, University of Genoa, Viale Benedetto XV, Genoa, Italy.
(7)University of Nottingham, University Park, Nottingham, UK.
(8)Pain Centre Versus Arthritis, Clinical Sciences Building, City Hospital, 
Nottingham, UK.
(9)Primary Integrated Community Services, Nottingham, UK.
(10)Clinical Pharmacology Department, PIC/CIC Inserm 1405-University Hospital 
CHU and Faculty of Medicine, Université Clermont Auvergne, Clermont-Ferrand, 
France.
(11)Department for Pain Research and Treatment, Medical College Jagiellonian 
University, Krakow, Poland.

Pharmacological pain treatment in older persons is presented by a 
multi-disciplinary group of European pain experts. Drugs recommended for acute 
or chronic nociceptive pain, also for neuropathic pain and the routes of 
administration of choice are the same as those prescribed for younger persons 
but comorbidities and polypharmacy in older persons increase the risk of adverse 
effects and drug interactions. Not all drugs are available or authorised in all 
European countries. For mild-to-moderate pain, non-opioids including paracetamol 
and non-steroidal anti-inflammatory drugs are first-line treatments, followed by 
nefopam and metamizole. Codeine, dihydrocodeine and tramadol are prescribed for 
moderate to severe pain and 'strong' opioids, including morphine, hydromorphone, 
oxycodone, fentanyl, buprenorphine, methadone and tapentadol, for severe pain. 
Chronic neuropathic pain treatment relies on coanalgesics, including 
anti-epileptics (gabapentinoids) and anti-depressants with additional option of 
topical lidocaine and capsaicine. The choice of analgesic(s) and the route of 
administration should be guided by the pain characteristics, as well as by the 
patient's comorbidities, organ function and medications. Several directions have 
been highlighted to optimise pharmacological pain management in older 
individuals: (1) before starting pain treatment adequately detect and assess 
pain and always perform a full geriatric assessment, (2) consider kidney 
function systematically to adjust the doses of analgesics and avoid the risks of 
overdose, (3) start with the lowest dose of an analgesic and increase it 
gradually under the control of the effect, (4) involve the older persons and 
family in their treatment, (5) reevaluate pain regularly during treatment and 
(6) combine pharmacological treatment with non-pharmacological approaches.

© 2024. The Author(s).

DOI: 10.1007/s40266-024-01151-8
PMID: 39465454


5. Clin Pharmacokinet. 2024 Oct 23. doi: 10.1007/s40262-024-01433-9. Online ahead
 of print.

Population Pharmacokinetic Quantification of CYP2D6 Activity in Codeine 
Metabolism in Ambulatory Surgical Patients for Model-Informed Precision Dosing.

Ashraf MW(#)(1), Poikola S(#)(2), Neuvonen M(3)(4), Kiiski JI(3)(4), Kontinen 
VK(2), Olkkola KT(5), Backman JT(3)(4)(6), Niemi M(3)(4)(6), Saari TI(7)(8).

Author information:
(1)Department of Anaesthesiology and Intensive Care, University of Turku, 
Kiinamyllynkatu 4-8, P.O. Box 52, 20520, Turku, Finland.
(2)Division of Anaesthesiology, Department of Anaesthesiology, Intensive Care 
and Pain Medicine, Jorvi Hospital, University of Helsinki, HUS Helsinki 
University Hospital, Helsinki, Finland.
(3)Department of Clinical Pharmacology, Faculty of Medicine, University of 
Helsinki, Helsinki, Finland.
(4)Individualized Drug Therapy Research Program, Faculty of Medicine, University 
of Helsinki, Helsinki, Finland.
(5)Department of Anaesthesiology, Intensive Care and Pain Medicine, University 
of Helsinki, HUS Helsinki University Hospital, Helsinki, Finland.
(6)Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki 
University Hospital, Helsinki, Finland.
(7)Department of Anaesthesiology and Intensive Care, University of Turku, 
Kiinamyllynkatu 4-8, P.O. Box 52, 20520, Turku, Finland. teisaa@utu.fi.
(8)Division of Perioperative Services, Intensive Care and Pain Medicine, Turku 
University Hospital, Turku, Finland. teisaa@utu.fi.
(#)Contributed equally

BACKGROUND AND OBJECTIVE: Codeine metabolism in humans is complex due to the 
involvement of multiple cytochrome P450 (CYP) enzymes, and has a strong genetic 
underpinning, which determines the levels of relevant CYP450 enzyme expression 
in vivo. Polymorphic CYP2D6 metabolises codeine to morphine via O-demethylation, 
while a strong correlation between CYP2D6 phenotype and opioidergic adverse 
effects of codeine is well documented. The aim of this study was to quantify the 
effect of CYP2D6 genotype on the biotransformation of codeine.
METHODS: We conducted a prospective clinical trial with 1000 patients, during 
which ambulatory patients were administered 60 mg of codeine preoperatively and 
the association between CYP2D6 activity and morphine exposure across various 
CYP2D6 genotypes was quantified using a population pharmacokinetic model. Plasma 
concentration data for codeine and its primary metabolites were obtained from 
997 patients and CYP2D6 genotype was screened for study subjects, and respective 
sums of activity scores assigned for each CYP2D6 allele were used as covariates 
in model development.
RESULTS: Our final model predicts the disposition of codeine and the formation 
of morphine, codeine-6-glucuronide and morphine-3-glucuronide adequately while 
accounting for variability in morphine exposure on the basis of CYP2D6 genotype. 
In agreement with previous results, patients with decreased function alleles 
(CYP2D6*10 and *41) showed varying levels of decrease in CYP2D6 activity that 
were inconsistent with increasing activity scores. Model simulations demonstrate 
that morphine concentrations in ultrarapid CYP2D6 metabolisers reach systemic 
concentrations that can potentially cause respiratory depression (over 9.1 
ng/mL), and have 218% higher exposure (19 versus 8.7 µg · h/L, p < 0.001) to 
morphine than normal metabolisers. Similarly, poor and intermediate metabolisers 
had significantly reduced morphine exposure (1.0 and 3.7 versus 8.7 µg · h/L, p 
< 0.001) as compared with normal metabolisers.
CONCLUSIONS: Our final model leads the way in implementing model-informed 
precision dosing in codeine therapy and identifies the use of genetic testing as 
an integral component in the effort to implement rational pharmacotherapy with 
codeine.

© 2024. The Author(s).

DOI: 10.1007/s40262-024-01433-9
PMID: 39441506