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Purpose CYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of CYP2D6-guided opioid prescribing on pain control. Methods Participants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided ( n  = 235) or usual care ( n  = 135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS ® measures. Results On stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine ( n  = 45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01 ± 1.59 vs. -0.40 ± 1.20; adj P  = 0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61 ± 1.39) and usual care (-0.54 ± 1.69) groups (adj P  = 0.540). Conclusion These data support the potential benefits of CYP2D6-guided pain management.

PurposeEffect size estimates of analgesic drugs can be misleading. Ibuprofen (400 mg, 600 mg, 800 mg), paracetamol (1000 mg, 500 mg), paracetamol 1000 mg/codeine 60 mg, and placebo were investigated to establish the multidimensional pharmacodynamic profiles of each drug on acute pain with calculated effect size estimates.MethodsA randomized, double-blind, single-dose, placebo-controlled, parallel-group, single-centre, outpatient, and single-dose study used 350 patients (mean age 25 year, range 18 to 30 years) of homogenous ethnicity after third molar surgery. Primary outcome was sum pain intensity over 6 h. Secondary outcomes were time to analgesic onset, duration of analgesia, time to rescue drug intake, number of patients taking rescue drug, sum pain intensity difference, maximum pain intensity difference, time to maximum pain intensity difference, number needed to treat values, adverse effects, overall drug assessment as patient-reported outcome measure (PROM), and the effect size estimates NNT and NNTp.ResultsIbuprofen doses above 400 mg do not significantly increase analgesic effect. Paracetamol has a very flat analgesic dose–response profile. Paracetamol 1000/codeine 60 mg gives similar analgesia as ibuprofen from 400 mg, but has a shorter time to analgesic onset. Active drugs show no significant difference in maximal analgesic effect. Other secondary outcomes support these findings. The frequencies of adverse effects were low, mild to moderate in all active groups. NNT and NTTp values did not coincide well with PROMs.ConclusionIbuprofen doses above 400 mg for acute pain offer limited analgesic gain. Paracetamol 1000 mg/codeine 60 mg is comparable to ibuprofen doses from 400 mg. Calculated effect size estimates and PROM in our study seem not to relate well as clinical analgesic efficacy estimators.Trial registrationNCT00699114.

This trial aimed to identify the effects of providing pharmacogenomic (PGx) results and recommendations for patients with chronic pain treated in primary care practices compared to standard care. An open‐label, prospective, largely virtual, type‐2 hybrid effectiveness trial randomized participants to PGx or standard care arms. Adults with pain ≥ 3 months who were treated with tramadol, codeine, or hydrocodone enrolled. Alternative analgesics were recommended for CYP2D6 intermediate or poor metabolizers (IM/PMs). Prescribing decisions were at providers' discretion. The trial randomized 253 participants. A modified intent‐to‐treat primary analysis assessed change in pain intensity over 3 months among IM/PMs (PGx: 49; Standard care: 57). The PGx and standard care arms showed no difference in pain intensity change (−0.10 ± 0.63 vs. −0.21 ± 0.75 standard deviation; p = 0.74) or PGx‐aligned care (69% vs. 63%; standardized difference [SD] = 0.13). In IM/PMs, secondary analyses of pain intensity change suggested improvements with PGx‐aligned (n = 70; −0.21 ± 0.70) vs. unaligned care (n = 36; −0.06 ± 0.69) (SD = −0.22), with this difference increasing when examining IM/PMs with an analgesic change (aligned: n = 31, −0.28 ± 0.76; unaligned: n = 36, −0.06 ± 0.69; SD = −0.31). This approach to PGx implementation for chronic pain was not associated with different prescribing (i.e., similar proportions of PGx‐aligned care) or clinical outcomes. Secondary analyses suggest that prescribing aligned with PGx recommendations showed a small improvement in pain intensity. However, the proportion of patients with a clinically meaningful improvement (≥ 30%) in pain intensity was similar. Future efforts should identify effective implementation methods.

Objective To compare the analgesic efficacy and side effects of the synthetic cannabinoid nabilone with those of the weak opioid dihydrocodeine for chronic neuropathic pain. Design Randomised, double blind, crossover trial of 14 weeks’ duration comparing dihydrocodeine and nabilone.Setting Outpatient units of three hospitals in the United Kingdom.Participants 96 patients with chronic neuropathic pain, aged 23-84 years. Main outcome measures The primary outcome was difference between nabilone and dihydrocodeine in pain, as measured by the mean visual analogue score computed over the last 2 weeks of each treatment period. Secondary outcomes were changes in mood, quality of life, sleep, and psychometric function. Side effects were measured by a questionnaire.Intervention Patients received a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone at the end of each escalating treatment period of 6 weeks. Treatment periods were separated by a 2 week washout period.Results Mean baseline visual analogue score was 69.6 mm (range 29.4-95.2) on a 0-100 mm scale. 73 patients were included in the available case analysis and 64 patients in the per protocol analysis. The mean score was 6.0 mm longer for nabilone than for dihydrocodeine (95% confidence interval 1.4 to 10.5) in the available case analysis and 5.6 mm (10.3 to 0.8) in the per protocol analysis. Side effects were more frequent with nabilone.Conclusion Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone and had slightly fewer side effects, although no major adverse events occurred for either drug. Trial registration Current Controlled Trials ISRCTN15330757.

The aim of this study was to evaluate the efficacy of naproxen sodium + codeine phosphate and dexketoprofen trometamol + paracetamol combinations in the treatment of acute dental pain during the preoperative period. Patients with complaints of acute pericoronitis caused by a semi-erupted lower impacted third molar were included in the study. Patients were randomly divided into two groups, naproxen sodium + codeine phosphate (550/30 mg) in group A and dexketoprofen trometamol + paracetamol (25/300 mg) in group B, and pain was assessed by VAS. The collected data were statistically analysed and interpreted using SPSS. The Friedman test (a non-parametric test) was used to analyse data within groups. The independent groups t-test and Mann–Whitney U-test were used to analyse data between groups. Of the 62 patients included in the study, 51 (82.3%) were female and 11 (17.7%) were male, with a mean age of 22.94 years. As a result of the 7-day evaluation, the VAS average in group A decreased from 7.61 to 1.26, representing an 83.44% decrease, while in group B, it decreased from 7.19 to 0.61, representing an 91.52% decrease. When the VAS averages of groups A and B were compared over time, statistically significant differences were only found between the values on day 7 ( p  < 0.05). Both analgesics were effective in acute dental pain. The results of this study support the use of dexketoprofen trometamol + paracetamol and naproxen sodium + codeine phosphate combinations in the treatment of acute dental pain during preoperative period.  Clinical Trial Registration: This trial was retrospectively registered on http://www.clinicaltrials.gov/ on 21 March 2025 under the title ‘Evaluation of the Analgesic Efficacy of the Combination of Dexketoprofen + Paracetamol and the Combination of Naproxen Sodium + Codeine in Patients With Acute Dental Pain’ and number NCT06916234.

Codeine is an analgesic drug acting on μ -opiate receptors predominantly via its metabolite morphine, which is formed almost exclusively by the genetically polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Whereas it is known that individuals lacking CYP2D6 activity (poor metabolizers, PM) suffer from poor analgesia from codeine, ultra-fast metabolizers (UM) due to the CYP2D6 gene duplication may experience exaggerated and even potentially dangerous opioidergic effects and no systematical study has been performed so far on this question. A single dose of 30 mg codeine was administered to 12 UM of CYP2D6 substrates carrying a CYP2D6 gene duplication, 11 extensive metabolizers (EM) and three PM. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism methods and a single-base primer extension method for characterization of the gene-duplication alleles. Pharmacokinetics was measured over 24 h after drug intake and codeine and its metabolites in plasma and urine were analyzed by liquid chromatography with tandem mass spectrometry. Significant differences between the EM and UM groups were detected in areas under the plasma concentration versus time curves (AUCs) of morphine with a median (range) AUC of 11 (5–17)  μ g h l −1 in EMs and 16 (10–24) μ g h l −1 in UM ( P =0.02). In urine collected over 12 h, the metabolic ratios of the codeine+codeine-6-glucuronide divided by the sum of morphine+its glucuronides metabolites were 11 (6–17) in EMs and 9 (6–16) in UM ( P =0.05). Ten of the 11 CYP2D6 UMs felt sedation (91%) compared to six (50%) of the 12 EMs ( P =0.03). CYP2D6 genotypes predicting ultrarapid metabolism resulted in about 50% higher plasma concentrations of morphine and its glucuronides compared with the EM. No severe adverse effects were seen in the UMs in our study most likely because we used for safety reasons a low dose of only 30 mg. It might be good if physicians would know about the CYP2D6 duplication genotype of their patients before administering codeine.

Codeine, a 3-methylmorphine, and other related opioids have been implicated in androgen suppression, although the associated mechanisms remain unclear. Therefore, the objective of the current study was to elucidate the in vivo molecular mechanisms underlying codeine-induced androgen suppression. This study made use of twenty-one healthy male rabbits, distributed into three groups randomly, control and codeine-treated groups. The control had 1ml of normal saline daily p.o. The codeine-treated groups received either 4mg/kg b.w of codeine or 10mg/kg b.w of codeine p.o. for six weeks. Reproductive hormonal profile, testicular weight, testicular enzymes, oxidative and inflammatory parameters, testicular DNA fragmentation, histological examination and apoptosis marker were evaluated to examine the effects of codeine use. Oral administration of codeine resulted in testicular atrophy and alterations in testicular histomorphology, elevated testicular enzymes, and suppression of circulatory and intra-testicular testosterone. These changes were associated with a marked rise in oxidative markers and decline in the activities of testicular enzymatic antioxidants, as well as oxidative DNA damage, inflammatory response, testicular DNA fragmentation, and caspase-dependent apoptosis (p<0.05). In conclusion, chronic codeine use resulted in testicular degeneration and testosterone suppression, which is attributable to TNF-α/nitric oxide-/oxidative stress-mediated caspase-dependent apoptotic testicular cell death and loss of testicular function.

Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand on the subject outlined by the authors focusing on abuse prevention and prevalence rates. The reviewed literature was identified in several online databases through searches conducted with phrases created by combining the international non-proprietary names of the drugs with terms related to drug misuse. The results show that OTC opioids are misused as an alternative for illicit narcotics, or prescription-only opioids. The potency of codeine and loperamide is strongly dependent on the individual enzymatic activity of CYP2D6 and CYP3A4, as well as P-glycoprotein function. Codeine can also be utilized as a substrate for clandestine syntheses of more potent drugs of abuse, namely desomorphine (“Krokodil”), and morphine. The dangerous methods used to prepare these substances can result in poisoning from toxic chemicals and impurities originating from the synthesis procedure. OTC opioids are generally safe when consumed in accordance with medical guidelines. However, the intake of supratherapeutic amounts of these substances may reveal surprising traits of common medications.

Hair analysis for drugs has become extensively used for forensic investigation in recent years. To best interpret hair drug content in post-mortem conditions, the extent of external contamination by biological fluids, such as blood, must be taken into account to avoid false positive results. The present study evaluated opiates and opioids incorporation into hair from blood containing different concentrations of morphine (MOR), 6-mono-acetyl morphine (6-AM), codeine (COD), dihydrocodeine (DHC), tramadol (TRA), oxycodone (OXY), methadone (MET), 2-ethylidene-1,5-dimethyl-3,3- diphenyl pyrrolidine (EDDP), buprenorphine (BUP) and norbuprenorphine (NBUP). The hair strands contaminated by brief soaking into blood were stored at room temperature (RT) or at 4°C during 6 hours, 1, 3, 7 or 14 days. After decontamination by extensive washing, we show that all opiates and opioids were incorporated into hair within a few hours at RT and 4°C, without significant changes over time. The concentrations of opiates and opioids in hair reached the cut-off levels established by the Society of Hair Testing (SoHT) for therapeutic (MET, COD), or toxic or lethal (all other molecules) blood concentrations. The metabolite to parent drug concentration ratios were determined for NBUP/BUP, MOR/6-AM and EDDP/MET and could be helpful as indicators of blood external contamination. •Opiates and opioids incorporate deeply into hair after short exposure to blood.•No influence of temperature of storage on opiates and opioids integration into hair.•Avoid analyzing hair samples contaminated with blood containing opiates and opioids.•Metabolite to parent drug ratio could be helpful as indicator of hair contamination.

Codeine is derived from morphine, an opioid analgesic, and has weaker analgesic and sedative effects than the parent molecule. This weak opioid is commonly used in combination with other drugs for over-the-counter cough relief medication. Due to the psychoactive properties of opioid drugs, the easily obtained codeine often becomes subject to misuse. Codeine misuse has emerged as a concerning public health issue due to its associated adverse effects such as headache, nausea, vomiting, and hemorrhage. Thus, it is very important to develop reliable analytical techniques to detect codeine for both quality control of pharmaceutical formulations and identifying drug misuse in the community. This review aims to provide critical outlooks on analytical methods applicable to the determination of codeine.