Comparative safety of tramadol and other opioids following total hip and knee arthroplasty.

BACKGROUND: Tramadol is increasingly used to treat acute postoperative pain among older adults following total hip and knee arthroplasty (THA/TKA). However, tramadol has a complex pharmacology and may be no safer than full opioid agonists. We compared the safety of tramadol, oxycodone, and hydrocodone among opioid-naïve older adults following elective THA/TKA. METHODS: This retrospective cohort included Medicare Fee-for-Service beneficiaries ≥ 65 years with elective THA/TKA between January 1, 2010 and September 30, 2015, 12 months of continuous Parts A and B enrollment, 6 months of continuous Part D enrollment, and no opioid use in the 6 months prior to THA/TKA. Participants initiated single-opioid therapy with tramadol, oxycodone, or hydrocodone within 7 days of discharge from THA/TKA hospitalization, regardless of concurrently administered nonopioid analgesics. Outcomes of interest included all-cause hospitalizations or emergency department visits (serious adverse events (SAEs)) and a composite of 10 surgical- and opioid-related SAEs within 90-days of THA/TKA. The intention-to-treat (ITT) and per-protocol (PP) hazard ratios (HRs) for tramadol versus other opioids were estimated using inverse-probability-of-treatment-weighted pooled logistic regression models. RESULTS: The study population included 2,697 tramadol, 11,407 oxycodone, and 14,665 hydrocodone initiators. Compared to oxycodone, tramadol increased the rate of all-cause SAEs in ITT analyses only (ITT HR 1.19, 95%CLs, 1.02, 1.41; PP HR 1.05, 95%CLs, 0.86, 1.29). Rates of composite SAEs were not significant across comparisons. Compared to hydrocodone, tramadol increased the rate of all-cause SAEs in the ITT and PP analyses (ITT HR 1.40, 95%CLs, 1.10, 1.76; PP HR 1.34, 95%CLs, 1.03, 1.75), but rates of composite SAEs were not significant across comparisons. CONCLUSIONS: Postoperative tramadol was associated with increased rates of all-cause SAEs, but not composite SAEs, compared to oxycodone and hydrocodone. Tramadol does not appear to have a superior safety profile and should not be preferentially prescribed to opioid-naïve older adults following THA/TKA.

Evaluation of histological and ultrastructural changes provoked by prenatal tramadol on postnatal cortical cerebellar neuronal development in rats: possible implication of Ki67, GFAP and MicroRNA-7/P53 signalling trajectories.

Tramadol is a novel centrally acting analgesic. Despite, its implementation during pregnancy may impair neuronal survival and synaptic development in neonatal cerebella. The current investigation assessed the histological and ultrastructural alterations in postnatal cortical cerebellar neuronal development induced by prenatal tramadol. 30 offsprings were divided to control group I: fifteen pups born to mothers given saline from D10 till D21 of gestation. Tramadol-treated group II: fifteen pups born to mothers received tramadol HCL (50 mg/kg/day) from D10 till D21 of gestation. Pups were categorized into three subgroups (a, b, and c) and offered for sacrifice on the seventh, fourteenth and twenty-first post-natal days. Light microscopic examination revealed the overcrowding and signs of red degeneration affecting purkinje cell layer. Neurodegenerative signs of both purkinje and granule cell neurons were also confirmed by TEM in form of chromatin condensation, dilated Golgi channels, disrupted endoplasmic reticulum, marked infolding of the nuclear envelope and decrease in granule cell precursors. In addition, the astrocytic processes and terminal nerve axons appeared with different degrees of demyelination and decreased number of oligodendrocytes and degenerated mitochondria. Furthermore, group II exhibited an increase in P53 immune expression. The area percentage of apoptotic cells detected by TUNEL assay was significantly increased. Besides to the significant decrease of Ki67 immunoreactivity in the stem neuronal cell progenitors. Quantitative PCR results showed a significant decline in micro RNA7 gene expression in tramadol treated groups resulting in affection of multiple target genes in P53 signaling pathways, improper cortical size and defect in neuronal development.

Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants.

Concurrent use of skeletal muscle relaxants (SMRs) and opioids has been linked to an increased risk of injury. However, it remains unclear whether the injury risks differ by specific SMR when combined with opioids. We conducted nine retrospective cohort studies within a US Medicaid population. Each cohort consisted exclusively of person-time exposed to both an SMR and one of the three most dispensed opioids-hydrocodone, oxycodone, and tramadol. Opioid users were further divided into three cohorts based on the initiation order of SMRs and opioids-synchronically triggered, opioid-triggered, and SMR-triggered. Within each cohort, we used Cox proportional hazard models to compare the injury rates for different SMRs compared to methocarbamol, adjusting for covariates. We identified 349,543, 139,458, and 218,967 concurrent users of SMRs with hydrocodone, oxycodone, and tramadol, respectively. In the oxycodone-SMR-triggered cohort, the adjusted hazard ratios (HRs) were 1.86 (95% CI, 1.23-2.82) for carisoprodol and 1.73 (1.09-2.73) for tizanidine. In the tramadol-synchronically triggered cohort, the adjusted HRs were 0.69 (0.49-0.97) for metaxalone and 0.62 (0.42-0.90) for tizanidine. In the tramadol-SMR-triggered cohort, the adjusted HRs were 1.51 (1.01-2.26) for baclofen and 1.48 (1.03-2.11) for cyclobenzaprine. All other HRs were statistically nonsignificant. In conclusion, the relative injury rate associated with different SMRs used concurrently with the three most dispensed opioids appears to vary depending on the specific opioid and the order of combination initiation. If confirmed by future studies, clinicians should consider the varying injury rates when prescribing SMRs to individuals using hydrocodone, oxycodone, and tramadol.

Tramadol-warfarin interaction.

Overview of: Danbury G Susan Gladstone: Prevention of future deaths report [online], 2023. Available: https://www.judiciary. uk/​prevention-​of-​future-​death-​reports/​susan-​gladstone-​prevention-​offuture-​deaths-​report/ [Accessed 8 January 2024].

Opioids in geriatric units in 14 Belgian hospitals: prevalence, dosage and associated factors.

Introduction: Adverse effects of opioids are common among older individuals, and undertreatment as well as overuse can be an issue. Epidemiological data on opioid use in older individuals are available, but scarce in hospitalized patients.Aims: The aim of this study is to examine the one-day prevalence of opioid use among older inpatients and identify the factors associated with both opioid use and dosage.Materials and methods: One-day cross-sectional study with data collected from geriatric units across 14 Belgian hospitals. The primary focus of the study is to assess the prevalence of opioid use and dosage, along with identifying associated factors. To achieve this, a multiple binary logistic regression model was fitted for opioid use, and a multiple linear regression model for opioid dose.Results: Opioids were used in 24.4% of 784 patients, of which 57.9% was treated with tramadol, 13.2% with oxycodone or morphine and 28.9% with transdermal buprenorphine or fentanyl. The odds for opioid use were 4.2 times higher in patients in orthogeriatric units compared to other patients (OR=4.2, 95% CI=2.50-7.05). The prevalence of opioid use was 34% higher in patients without dementia compared to patients with dementia (OR=0.66, 95% CI=0.46-0.95). The overall mean daily dosage was 14.07mg subcutaneous morphine equivalent. After adjustment for age, gender and dementia, dosage was only associated with type of opioid: the estimated mean opioid dose was 70% lower with tramadol (mean ratio=0,30,95% CI=0,23-0,39) and 67% lower with oxycodone and morphine (mean ratio=0,33, 95% CI=0,22-0,48) compared to transdermal buprenorphine and transdermal fentanyl.Conclusions: One in four patients received opioid treatment. It is not clear whether this reflects under- or overtreatment, but these results can serve as a benchmark for geriatric units to guide future pain management practices. The utilization of transdermal fentanyl and buprenorphine, resulting in higher doses of morphine equivalent, poses significant risks for side effects.

Co-crystal of Tramadol-Celecoxib Versus Tramadol or Placebo for Acute Moderate-to-Severe Pain After Oral Surgery: Randomized, Double-Blind, Phase 3 Trial (STARDOM1).

INTRODUCTION: Co-crystal of tramadol-celecoxib (CTC) is the first analgesic co-crystal for acute pain. This completed phase 3 multicenter, double-blind trial assessed the efficacy and safety/tolerability of CTC in comparison with that of tramadol in the setting of moderate-to-severe pain up to 72 h after elective third molar extraction requiring bone removal. METHODS: Adults (n = 726) were assigned randomly to five groups (2:2:2:2:1): orally administered twice-daily CTC 100 mg (44 mg rac-tramadol hydrochloride/56 mg celecoxib; n = 164), 150 mg (66/84 mg; n = 160) or 200 mg (88/112 mg; n = 160); tramadol 100 mg four times daily (n = 159); or placebo four times daily (n = 83). Participants in CTC groups also received twice-daily placebo. The full analysis set included all participants who underwent randomization. The primary endpoint was the sum of pain intensity differences over 0 to 4 h (SPID0-4; visual analog scale). Key secondary endpoints included 4-h 50% responder and rescue medication use rates. Safety endpoints included adverse events (AEs), laboratory measures, and Opioid-Related Symptom Distress Scale (OR-SDS) score. RESULTS: All CTC doses were superior to placebo (P < 0.001) for primary and key secondary endpoints. All were superior to tramadol for SPID0-4 (analysis of covariance least squares mean differences [95% confidence interval]: - 37.1 [- 56.5, - 17.6], - 40.2 [- 59.7, - 20.6], and - 41.7 [- 61.2, - 22.2] for 100, 150, and 200 mg CTC, respectively; P < 0.001) and 4-h 50% responder rate. Four-hour 50% responder rates were 32.9% (CTC 100 mg), 33.8% (CTC 150 mg), 40.6% (CTC 200 mg), 20.1% (tramadol), and 7.2% (placebo). Rescue medication use was lower in the 100-mg (P = 0.013) and 200-mg (P = 0.003) CTC groups versus tramadol group. AE incidence and OR-SDS scores were highest for tramadol alone. CONCLUSIONS: CTC demonstrated superior pain relief compared with tramadol or placebo, as well as an improved benefit/risk profile versus tramadol. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02982161; EudraCT number, 2016-000592-24.

Co-crystal of tramadol-celecoxib (CTC) for acute moderate-to-severe pain.

OBJECTIVE: This narrative review aims to provide a clinical perspective on the potential role of co-crystal of tramadol-celecoxib (CTC) in the management of acute moderate-to-severe pain by synthesizing the available preclinical and clinical data, with emphasis on phase 3 trials. METHODS: A non-systematic literature review was performed using a targeted PubMed search for articles published between January 1, 2000, and May 2, 2023; all publication types were permitted, and selected articles were limited to those published in English. Search results were manually reviewed to identify references based on their preclinical and clinical relevance to CTC and management of acute moderate-to-severe pain. RESULTS: The crystalline structure of CTC alters the physicochemical properties of tramadol and celecoxib, modifying their pharmacokinetics. If taken in a free combination, tramadol reduces absorption of celecoxib. Conversely, administration of CTC slows tramadol absorption and lowers its maximum plasma concentration, while increasing celecoxib plasma concentration through its enhanced release. In clinical studies across models of acute moderate-to-severe pain, CTC demonstrated an early onset of analgesia, with improved efficacy and lower rescue medication use, compared with either agent alone. CTC's safety profile was in line with that expected for the individual components; no additive effects were observed. CTC exhibited tramadol-sparing effects, with efficacy seen at lower daily/cumulative opioid doses vs. tramadol alone. CONCLUSIONS: Results from phase 3 trials suggest that the modified physicochemical properties of tramadol and celecoxib in CTC translate into an improved clinical benefit-risk profile, including fewer opioid-related adverse effects due to lower overall opioid dosing.

A consideration of CYP2D6 genetic variations in the Ghanaian population as a potential 'culprit' for the tramadol 'abuse crisis'.

BACKGROUND: Cytochrome P450 2D6 is involved in the metabolism of several important medicines including opioids. Variations in CYP2D6 have been implicated in drug response and according to the Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, dosing for CYP2D6 substrates should be based on variants carried by individuals. Although CYP2D6 variations in Ghana had been previously recorded, not all variants have been reported in the Ghanaian population. In this exploratory study we set to investigate certain unreported variations in the Ghanaian population in addition to the previously reported ones and use that to understand the tramadol 'abuse' crisis that is currently being experienced in Ghana. METHODS: This study employed a convenience sampling approach to include 106 unrelated participants who were recruited as part of the PHARMABIOME project. We successfully genotyped 106 samples using Iplex GOLD SNP genotyping protocol after extracting DNA from these individuals. Allele and diplotype frequencies were undertaken by counting from observed genotypes. Comparison of alleles reported from various studies were done. RESULTS: Unreported alleles such as *3, *9 and *41 which are classified as no function and decreased function were observed in our study cohort. In addition, variants such as (*1, *2, *4, *5, *10, *17 and *29 were observed with different frequencies. Our study showed 26% representation of intermediate metabolizers (IM) and 2% poor metabolizers (PM) in the study population. CONCLUSION: The implications for informal sector workers who use tramadol for recreational purposes, is that IMs and PMs will overdose as they may have reduced analgesic effects which will translate into increased risks of unforeseen adverse events. We therefore propose that CYP2D6 should be considered in opioid dosage while making use of these observed variations to implement new approaches to tackle the tramadol 'abuse crisis' in Ghana.

Tramadol use before total shoulder arthroplasty: patients have lower risk of complications and resource utilization than those using traditional opioids.

BACKGROUND: Evidence continues to mount for the deleterious effects of preoperative opioid use in the setting of total shoulder arthroplasty (TSA). Tramadol, a synthetic opioid with concomitant neurotransmitter effects, has become a popular alternative to traditional opioids, but it has not been well studied in the preoperative setting of TSA. The purpose of this study is to evaluate postsurgical outcomes in TSA for patients with preoperative tramadol use compared with patients using traditional opioids and those who were opioid naïve. METHODS: Using the IBM Watson Health MarketScan databases, a retrospective cohort study was performed for patients who underwent TSA from 2009 to 2018. Filled pain prescriptions were collected, and prescribing trends were analyzed. Outcomes were compared between 4 patient cohorts defined by preoperative analgesia use-opioid naïve, tramadol, traditional opioids, and combination (opioids and tramadol). Multivariate analysis was used to account for small variations in cohort demographics and comorbidities. Analysis focused on resource utilization and complications. Revision rates at 1 and 3 years postoperatively were also compared. RESULTS: A total of 29,454 TSA patients were studied, with 8959 available for 3-year postoperative follow-up. Of these, 10,462 (35.5%) were prescribed traditional opioids and 2214 (7.5%) tramadol only. From 2009 to 2018, prescribing trends in the United States demonstrated a significant decrease in the number of patients prescribed preoperative narcotics, whereas the number of patients prescribed preoperative tramadol and those who were opioid naïve significantly increased. Compared with opioid-naïve patients, the traditional opioid cohort had significantly increased odds of resource utilization and complications, whereas the tramadol cohort did not. Specifically, the traditional opioid cohort had an increased risk of prosthetic joint infection compared with both opioid-naïve and tramadol cohorts. The traditional opioid cohort had higher revision rates than opioid-naïve patients at 1 and 3 years, whereas the tramadol cohort did not. CONCLUSION: Despite a decrease in opioid prescriptions over the study period, many patients in the United States remain on opioids. Although tramadol is not without its own risks, our results suggest that patients taking preoperative tramadol as an alternative to traditional opioids for glenohumeral arthritic pain had a lesser postoperative risk profile, comparable with opioid-naïve patients.

Association of tramadol use with risk of hip fractures in patients with osteoarthritis: A systematic review and meta-analysis of observational studies.

OBJECTIVE: Many studies have reported conflicting results for the use of tramadol with the risk of fractures, especially hip fractures. This systematic review and meta-analysis study aimed to evaluate the association of tramadol use versus codeine use with the risk of hip fracture for the first time. METHODS: PubMed, Scopus, Google Scholar, and Web of Science databases were searched with specific keywords to find studies that examined the association of tramadol use with hip fracture risk in patients with osteoarthritis up to May 2023. The risk of hip fracture secondary to tramadol versus codeine use was estimated based on age and sex. This systematic review was conducted based on the PRISMA checklist. Heterogeneity between studies was evaluated using Cochran's Q and I2 tests. Egger's test was used to check publication bias. The Newcastle-Ottawa Checklist (NOS) was used to assess the quality of the studies. FINDINGS: Ten studies with 1,939,293 participants were reviewed. The majority of participants were female. Based on the study evaluation checklist, most studies were of good quality. Tramadol use significantly increases the overall risk of hip fracture. (HR: 1.32, 95% CI: 1.14, 1.51, P: 0.001, I2:19.3%) Tramadol use significantly increases the risk of hip fracture in men (HR: 1.48, 95% CI: 1.24, 1.73, P: 0.001 I2:35%) and age ≤65 years (HR: 1.63, 95% CI: 1.45, 1.80, P: 0.001, I2:0%). CONCLUSION: The use of tramadol significantly increases the risk of hip fracture. This increased risk of hip fracture was greater in males younger than 65 years.

Exploring Perceptions About Paracetamol, Tramadol, and Codeine on Twitter Using Machine Learning: Quantitative and Qualitative Observational Study.

BACKGROUND: Paracetamol, codeine, and tramadol are commonly used to manage mild pain, and their availability without prescription or medical consultation raises concerns about potential opioid addiction. OBJECTIVE: This study aims to explore the perceptions and experiences of Twitter users concerning these drugs. METHODS: We analyzed the tweets in English or Spanish mentioning paracetamol, tramadol, or codeine posted between January 2019 and December 2020. Out of 152,056 tweets collected, 49,462 were excluded. The content was categorized using a codebook, distinguishing user types (patients, health care professionals, and institutions), and classifying medical content based on efficacy and adverse effects. Scientific accuracy and nonmedical content themes (commercial, economic, solidarity, and trivialization) were also assessed. A total of 1000 tweets for each drug were manually classified to train, test, and validate machine learning classifiers. RESULTS: Of classifiable tweets, 42,840 mentioned paracetamol and 42,131 mentioned weak opioids (tramadol or codeine). Patients accounted for 73.10% (60,771/83,129) of the tweets, while health care professionals and institutions received the highest like-tweet and tweet-retweet ratios. Medical content distribution significantly differed for each drug (P<.001). Nonmedical content dominated opioid tweets (23,871/32,307, 73.9%), while paracetamol tweets had a higher prevalence of medical content (33,943/50,822, 66.8%). Among medical content tweets, 80.8% (41,080/50,822) mentioned drug efficacy, with only 6.9% (3501/50,822) describing good or sufficient efficacy. Nonmedical content distribution also varied significantly among the different drugs (P<.001). CONCLUSIONS: Patients seeking relief from pain are highly interested in the effectiveness of drugs rather than potential side effects. Alarming trends include a significant number of tweets trivializing drug use and recreational purposes, along with a lack of awareness regarding side effects. Monitoring conversations related to analgesics on social media is essential due to common illegal web-based sales and purchases without prescriptions.

Clinical and Laboratory Factors Related to Seizure and Serotonin Toxicity in Tramadol Intoxication: An Egyptian Study.

BACKGROUND AND OBJECTIVES: Tramadol is a centrally acting analgesic with a lower risk of addiction compared to opioids. Tramadol overdose is becoming a health crisis in Egypt and is associated with serious and severe adverse effects. This study aims to identify clinical and laboratory findings associated with tramadol-induced seizure and serotonin toxicity in adult Egyptian patients with tramadol overdose. METHODS: This prospective study included adult patients admitted for tramadol overdose with or without symptoms of seizure or serotonin toxicity. Basic demographic information, clinical symptoms, laboratory measurements, and plasma tramadol concentrations were collected. RESULTS: A total of 71 patients (79% males) were included in the study. Seizure occurred in 38% of the subjects and was prevalent in male patients with metabolic acidosis or high tramadol concentrations. Serotonin toxicity occurred in 41% of the subjects and was prevalent in patients with hyperthermia, high pulse rate, and high tramadol levels. CONCLUSION: Seizure and serotonin toxicity are severe adverse effects of tramadol overdose that occur in high frequency among young Egyptians. High tramadol concentrations in plasma seem to play a key role in prevalence of seizure and serotonin syndrome in tramadol-intoxicated adult Egyptians.

Atypical Withdrawal Symptoms after Abrupt Tramadol Discontinuation: A Case Report.

Tramadol is a commonly utilized analgesic in the United States. One common misconception is that tramadol is safer than other opioid medications, or less likely to cause physical dependence. Given these misconceptions, the likelihood of patients experiencing withdrawal after discontinuation may be commonly overlooked as well. A 68-year old female patient with fibromyalgia was referred to a clinical pharmacy pain clinic for medication management. The patient was evaluated one month after abrupt discontinuation of tramadol 50 mg every 6 h for at least 10 years of use. She reports concerning symptoms of significant mucus production, fullness in chest and soreness in neck. Although tramadol is a Schedule IV Controlled Substance the risk of physical dependence and likelihood of patients experiencing withdrawal symptoms after abrupt cessation should not be diminished. Tramadol should not be considered a "safer" opioid therapy without potential of classic or atypical withdrawal symptoms, as well as risk of abuse, misuse or addiction.

Adverse Drug Reactions to Opioids: A Study in a National Pharmacovigilance Database.

INTRODUCTION: Opioids are commonly used as analgesics; however, like any medicine, they can produce adverse drug reactions (ADRs), including nausea, constipation, dependence, and respiratory depression, that result in harmful and fatal events. Therefore, it is essential to monitor the safety of these drugs in clinical practice. OBJECTIVE: This study aimed to characterize the safety profile of opioids by conducting a descriptive study based on a spontaneous reporting system (SRS) for ADRs in The Netherlands, focusing on abuse, misuse, medication errors, and differences between sexes. METHODS: Reports submitted to the Netherlands Pharmacovigilance Centre Lareb from January 2003 to December 2021 with an opioid drug as the suspected/interacting medicine were analyzed. Reporting odds ratios (RORs) for drug-ADR combinations were calculated, analyzed, and corrected for sex and drug utilization (expenditure) for the Dutch population. RESULTS: A total of 8769 reports were analyzed. Tramadol was the opioid with the most reports during the period (n = 2746), while oxycodone or tramadol had the highest number of reports per year in the study period. The most reported ADRs from opioid use were nausea, followed by dizziness and vomiting, independent of sex, and all of them were more often reported in women. Vomiting associated with tramadol (ROR females/males = 2.17) was significantly higher in women. Buprenorphine was responsible for most ADRs when corrected for expenditure, with high RORs observed with application site hypersensitivity, application site reaction, and application site rash. Fentanyl gave rise to most of the reports of ADRs concerning abuse, misuse, and medication errors. CONCLUSION: Patients treated with opioids experienced ADRs, primarily nausea, dizziness, and vomiting. For those groups of drugs, no significant differences were found between the sexes, except for the vomiting associated with tramadol. In general, ADRs related to opioids presented higher RORs when uncorrected and corrected for sexes and expenditure than other drugs. There was more disproportionate reporting for ADRs concerning abuse, misuse, and medication errors for opioids than other drugs in the Dutch SRS.

Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain.

Despite off-label use, the efficacy and safety of gabapentin and tramadol in pediatric patients (3 months to <18 years old) diagnosed with chronic pain has not been characterized. However, generating evidence based on randomized clinical trials in this population has been extremely challenging. The current investigation illustrates the use of clinical trial simulations (CTSs) as a tool for optimizing doses and protocol design for a prospective investigation in pediatric patients with chronic pain. Pharmacokinetic (PK) modeling and CTSs were used to describe the PKs of gabapentin and tramadol in the target population. In the absence of biomarkers of analgesia, systemic exposure (AUC, Css) was used to guide dose selection under the assumption of a comparable exposure-response (PKPD) relationship for either compound between adults and children. Two weight bands were identified for gabapentin, with doses titrated from 5 to 63 mg/kg. This yields gabapentin exposures (AUC0-8 ) of approximately 35 mg/L*h (1200 mg/day adult dose equivalent). For tramadol, median steady state concentrations between 200 and 300 ng/mL were achieved after doses of 2-5 mg/kg, but concentrations showed high interindividual variability. Simulation scenarios showed that titration steps are required to explore therapeutically relevant dose ranges taking into account the safety profile of both drugs. Gabapentin can be used t.i.d. at doses between 7-63 and 5-45 mg/kg for patients receiving gabapentin weighing <15 and ≥15 kg, respectively, whereas a t.i.d. regimen with doses between 1 and 5 mg/kg can be used for tramadol in patients who are not fast metabolisers.