Should Codeine Still be Considered a WHO Essential Medicine?

Codeine continues to be widely used as an analgesic, antidiarrhoeal and antitussive agent. Its analgesic effect depends on its biotransformation to morphine, a strong opioid. The highly variable biotransformation of codeine to morphine, catalysed by CYP2D6, underlies the pronounced interindividual variability of its analgesic response. Randomized controlled trials have demonstrated that codeine administered alone has the poorest analgesic effect among all commonly used analgesics in acute postoperative pain. Moreover, it is highly unlikely that the low dose of codeine contributes to the pain-relieving effect of the non-opioid component in combination analgesic products. In addition, there is a lack of reliable clinical evidence to support the use of codeine as an antitussive in acute or chronic cough. Codeine use, through its active metabolite morphine, has the potential to lead to abuse and dependence. The World Health Organization (WHO) removed codeine from the essential medicines list for children in 2011. Based on the available information in the scientific literature on the efficacy and safety of codeine, the WHO should seriously consider removing it also from the list of essential medicines for adults, which would be a strong signal for all health professionals to prescribe and dispense codeine with the utmost caution.

A candidate neuroimaging biomarker for detection of neurotransmission-related functional alterations and prediction of pharmacological analgesic response in chronic pain

BackgroundChronic pain is a world-wide clinical challenge. Response to analgesic treatment is limited and difficult to predict. Functional MRI (fMRI) has been suggested as a potential solution. However, while most analgesics target specific neurotransmission pathways, fMRI-based biomarkers are not specific for any neurotransmitter system, limiting our understanding of how they might contribute to predict treatment response.MethodsHere, we sought to bridge this gap by applying Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT) to investigate whether neurotransmission-enriched functional connectivity (FC) mapping can provide insights into the brain mechanisms underlying chronic pain and inter-individual differences in analgesic response after a placebo or duloxetine. Chronic knee osteoarthritis (OA) pain patients (n=56) underwent pre-treatment brain scans in two clinical trials. Study 1 (n=17) was a 2-week single-blinded placebo pill trial. Study 2 (n=39) was a 3-month double-blinded randomized trial comparing placebo to duloxetine, a dual serotonin-noradrenaline reuptake inhibitor.ResultsAcross two independent studies, we found that chronic pain OA patients present FC alterations in the FC related to the serotonin (SERT) and noradrenaline (NET) transporters, when compared to age-matched healthy controls. Placebo responders presented with higher pre-treatment dopamine transporter (DAT)-enriched FC than non-responders. Duloxetine responders presented with higher pre-treatment SERT and NET-enriched FC than non-responders. Pre-treatment SERT and NET-enriched FC achieved predictive positive values of duloxetine response up to 85.71%.ConclusionNeurotransmission-enriched FC mapping might hold promise as a new mechanistic-informed biomarker for functional brain alterations and prediction of response to pharmacological analgesia in chronic pain.

Pharmacogenomics and prescription opioid use

Genome-wide association studies and candidate gene findings suggest that genetic approaches may help in choosing the most appropriate drug and dosage, while preventing adverse drug reactions. This is the field that addresses Precision Medicine: to evaluate variations in the DNA sequence that could be responsible for different individual analgesic response. We review potential gene biomarkers with best overall convergent functional evidence, for opioid use, in pain management. Polymorphisms can modify pharmacodynamics (i.e., mu opioid receptor, OPRM1) and pharmacokinetics (i.e., CYP2D6 phenotypes) pathways altering opioid effectiveness, consumption, side effects or additionally, prescription opioid use dependence vulnerability. This review provides a summary of these candidate variants for the translation of genotype into clinically useful information in pain medicine.

Pain Biomarkers in Cancer: An Overview

Background: Pain is a common symptom in oncologic patients and its management is generally guided by pain individually perceived by patients and expressed through self-reported scales. However, the utility of these tools is limited because strongly dependent on patients’ opinions. For this reason, more objective instruments are desirable. Objective: In this overview scientific articles indicating potential markers to be used for pain management in cancer were collected and discussed. Methods: research was performed on principal electronic scientific databases by using the words “pain”, “cancer”, “markers” as “biomarkers” as the main keywords, and findings describing potential biomarkers for the management of cancer pain were reported. Results: Studies on pain markers not specific for cancer typology (inflammatory, genetic, markers predicting response to analgesic drugs, neuroimaging markers) and pain markers for specific types of cancer (bone cancer, breast cancer, lung cancer, head and neck cancer, prostate cancer, cancer in pediatrics) are presented and commented. Conclusion: This overview supports the view of the involvement of inflammatory mediators in the mechanisms underlying cancer pain. Up today only a few data from research on markers can help in the management of pain, except for pro-inflammatory cytokines and other inflammatory indexes such as C-reactive protein (CRP). However, biomarkers are a promising strategy useful to predict pain intensity and to purchase objective quantification of analgesic response in guiding decisions on individual-tailored treatments in cancer patients.