Pharmacogenetics of analgesic drugs

• Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined. • Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications. • While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype–phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor). • Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future. • This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors’ views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain

The Hansenula polymorpha PER8 Gene Encodes a Novel Peroxisomal Integral Membrane Protein Involved in Proliferation

We previously described the isolation of mutants of the methylotrophic yeast Hansenula polymorpha that are defective in peroxisome biogenesis. Here, we describe the characterization of one of these mutants, per8, and the cloning of the PER8 gene. In either methanol or methylamine medium, conditions that normally induce the organdies, per8 cells contain no peroxisome-like structures and peroxisomal enzymes are located in the cytosol. The sequence of PER8 predicts that its product (Per8p) is a novel polypeptide of 34 kD, and antibodies against Per8p recognize a protein of 31 kD. Analysis of the primary sequence of Per8p revealed a 39-amino-acid cysteine-rich segment with similarity to the C3HC4 family of zinc-finger motifs. Overexpression of PER8 results in a markedly enhanced increase in peroxisome numbers. We show that Per8p is an integral membrane protein of the peroxisome and that it is concentrated in the membranes of newly formed organdies. We propose that Per8p is a component of the molecular machinery that controls the proliferation of this organelle.

Circadian variation of pain as a measure of the analgesia requirements during the first 24-postoperative hours in patients using an opioid Patient Controlled Analgesia delivery system

Circadian rhythms have governed the everyday life of every single organism that has lived on Earth. The present study addresses the rhythms of cortisol and melatonin, their analgesic properties and the potential circadian rhythm of pain as a driver of the frequency of self-administered analgesia in postoperative patients with an opioid Patient Controlled Analgesia (PCA) delivery system. It aims to determine if acute 24-hour post-operative pain displays a circadian variation by analysing the number of times that patients self-administered morphine for pain relief and incidentally to determine if gender has any association with the frequency of self-administered analgesia. For that purpose, the frequencies of self-administered analgesia were divided into four periods of six hours each (three of them approximately corresponded to the day, and 1 to the night). A Multi-level Poisson regression analysis compared frequencies during period 4 (night) to all others (1, 2 and 3). The results show that there was a statistically significant difference between the frequencies of self-administered opioids in the night period compared to any other day period (p-value of <0.001, for periods 1, 2 and 3 respectively compared to period 4). Differences in terms of gender were also statistically significant (p < 0.001) with men’s opioid consumption almost double that of women’s but with much steeper rate of decline (p<0.001). These results may be partly explained by the rhythms of melatonin, cortisol and ß-endorphine, morphine’s chronopharmacology and possibly by oestrogen and progesterone

Mexiletine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L858F NaV 1.7 sodium channels.

The non-selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and became popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain-of-function SCN9a mutations benefit from a low systemic concentration of mexiletine, which usually does not induce adverse neurologic effects. The aim of this study was therefore to investigate the biophysical effects of mexiletine on the L858F primary erythromelalgia NaV 1.7 mutation in vitro

Magnetic Field scaling of Relaxation curves in Small Particle Systems

We study the effects of the magnetic field on the relaxation of the magnetization of small monodomain non-interacting particles with random orientations and distribution of anisotropy constants. Starting from a master equation, we build up an expression for the time dependence of the magnetization which takes into account thermal activation only over barriers separating energy minima, which, in our model, can be computed exactly from analytical expressions. Numerical calculations of the relaxation curves for different distribution widths, and under different magnetic fields H and temperatures T, have been performed. We show how a \svar scaling of the curves, at different T and for a given H, can be carried out after proper normalization of the data to the equilibrium magnetization. The resulting master curves are shown to be closely related to what we call effective energy barrier distributions, which, in our model, can be computed exactly from analytical expressions. The concept of effective distribution serves us as a basis for finding a scaling variable to scale relaxation curves at different H and a given T, thus showing that the field dependence of energy barriers can be also extracted from relaxation measurements.Comment: 12 pages, 9 figures, submitted to Phys. Rev.

Positive selection of novel peroxisome biogenesis-defective mutants of the yeast Pichia pastoris

We have developed two novel schemes for the direct selection of peroxisome-biogenesis-defective (pex) mutants of the methylotrophic yeast Pichia pastoris. Both schemes take advantage of our observation that methanol-induced pex mutants contain little or no alcohol oxidase (AOX) activity. AOX is a peroxisomal matrix enzyme that catalyzes the first step in the methanol-utilization pathway. One scheme utilizes allyl alcohol, a compound that is not toxic to cells but is oxidized by AOX to acrolein, a compound that is toxic. Exposure of mutagenized populations of AOX-induced cells to allyl alcohol selectively kills AOX-containing cells. However, pex mutants without AOX are able to grow. The second scheme utilizes a P. pastoris strain that is defective in formaldehyde dehydrogenase (FLD), a methanol pathway enzyme required to metabolize formaldehyde, the product of AOX. AOX-induced cells of fld1 strains are sensitive to methanol because of the accumulation of formaldehyde. However, fld1 pex mutants, with little active AOX, do not efficiently oxidize methanol to formaldehyde and therefore are not sensitive to methanol. Using these selections, new pex mutant alleles in previously identified PEX genes have been isolated along with mutants in three previously unidentified PEX group

Adverse effects of anti‐epileptics in trigeminal neuralgiform pain

Background: Side effects of anti‐epileptic drugs (AEDs) have not been adequately documented in trigeminal neuralgia and its variants. The aim of this observational cross‐sectional study was to compare the A‐B Neuropsychological Assessment Schedule (ABNAS), which measures cognitive side effects to the Adverse Events Profile (AEP), which looks at a broader range of side effects, and to investigate drug/dosage relationships with questionnaire scores to help determine a point at which a drug change would be indicated. / Methods: One hundred five patients were recruited from a facial pain clinic, over a 10‐month period. Self‐complete questionnaire scores were compared between patients using different AEDs. / Results: A‐B Neuropsychological Assessment Schedule score correlated well with AEP indicating that cognitive side effects were a significant burden. Toxic range on the ABNAS was estimated to occur when scores were >43/72 (95% CI: 37.4‐48.6). Polytherapy is weakly associated with the higher scores. Oxcarbazepine dosage was found to linearly correlate with AEP and ABNAS scores, better than carbamazepine dosage. Memory alteration was least common with lamotrigine and oxcarbazepine, and there was less association between fatigues with oxcarbazepine/pregabalin. / Conclusion: Anti‐epileptic drugs have significant side effects. The ABNAS questionnaire is a useful tool along with the AEP to recognize and monitor AEDs’ side effects and to help to adjust medications to optimal dosage

A Latent Propriospinal Network Can Restore Diaphragm Function After High Cervical Spinal Cord Injury

Spinal cord injury (SCI) above cervical level 4 disrupts descending axons from the medulla that innervate phrenic motor neurons, causing permanent paralysis of the diaphragm. Using an ex vivo preparation in neonatal mice, we have identified an excitatory spinal network that can direct phrenic motor bursting in the absence of medullary input. After complete cervical SCI, blockade of fast inhibitory synaptic transmission caused spontaneous, bilaterally coordinated phrenic bursting. Here, spinal cord glutamatergic neurons were both sufficient and necessary for the induction of phrenic bursts. Direct stimulation of phrenic motor neurons was insufficient to evoke burst activity. Transection and pharmacological manipulations showed that this spinal network acts independently of medullary circuits that normally generate inspiration, suggesting a distinct non-respiratory function. We further show that this “latent” network can be harnessed to restore diaphragm function after high cervical SCI in adult mice and rats