Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments.

Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the µ-opioid receptor, there are several differences in the pharmacology and neurobiology of oxycodone. The data that have emerged from the many efforts to analyze the pharmacological and molecular mechanism of oxycodone have generated considerable insight into its many actions, reviewed here, which, in turn, have provided new information on opioid receptor pharmacology. SIGNIFICANCE STATEMENT: Oxycodone, a µ-opioid receptor agonist, was synthesized in 1916 and introduced into clinical use in Germany in 1917. It has been studied extensively as a therapeutic analgesic for acute and chronic neuropathic pain as an alternative to morphine. Oxycodone emerged as a drug with widespread abuse. This article brings together an integrated, detailed review of the pharmacology of oxycodone, preclinical and clinical studies of pain and abuse, and recent advances to identify potential opioid analgesics without abuse liability.

Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial.

BACKGROUND: Opioid analgesics are commonly used for acute low back pain and neck pain, but supporting efficacy data are scarce. We aimed to investigate the efficacy and safety of a judicious short course of an opioid analgesic for acute low back pain and neck pain. METHODS: OPAL was a triple-blinded, placebo-controlled randomised trial that recruited adults (aged ≥18 years) presenting to one of 157 primary care or emergency department sites in Sydney, NSW, Australia, with 12 weeks or less of low back or neck pain (or both) of at least moderate pain severity. Participants were randomly assigned (1:1) using statistician-generated randomly permuted blocks to guideline-recommended care plus an opioid (oxycodone-naloxone, up to 20 mg oxycodone per day orally) or guideline-recommended care and an identical placebo, for up to 6 weeks. The primary outcome was pain severity at 6 weeks measured with the pain severity subscale of the Brief Pain Inventory (10-point scale), analysed in all eligible participants who provided at least one post-randomisation pain score, by use of a repeated measures linear mixed model. Safety was analysed in all randomly assigned eligible participants. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000775516). FINDINGS: Between Feb 29, 2016, and March 10, 2022, 347 participants were recruited (174 to the opioid group and 173 to the placebo group). 170 (49%) of 346 participants were female and 176 (51%) were male. 33 (19%) of 174 participants in the opioid group and 25 (15%) of 172 in the placebo group had discontinued from the trial by week 6, due to loss to follow-up and participant withdrawals. 151 participants in the opioid group and 159 in the placebo group were included in the primary analysis. Mean pain score at 6 weeks was 2·78 (SE 0·20) in the opioid group versus 2·25 (0·19) in the placebo group (adjusted mean difference 0·53, 95% CI -0·00 to 1·07, p=0·051). 61 (35%) of 174 participants in the opioid group reported at least one adverse event versus 51 (30%) of 172 in the placebo group (p=0·30), but more people in the opioid group reported opioid-related adverse events (eg, 13 [7·5%] of 174 participants in the opioid group reported constipation vs six [3·5%] of 173 in the placebo group). INTERPRETATION: Opioids should not be recommended for acute non-specific low back pain or neck pain given that we found no significant difference in pain severity compared with placebo. This finding calls for a change in the frequent use of opioids for these conditions. FUNDING: National Health and Medical Research Council, University of Sydney Faculty of Medicine and Health, and SafeWork SA.

The Effects of Chronic Naltrexone on Reinstatement of Opioid-Induced Drug-Seeking Behavior and Antinociception.

Opioid addiction is a chronic relapsing disorder in which drug-seeking behavior during abstinence can be provoked by exposure to a µ-opioid receptor (MOR) agonist or opioid-associated cues. Opioid self-administration behavior in laboratory subjects can be reinstated by priming with MOR agonists or agonist-related stimuli, providing a procedure suitable for relapse-related studies. The opioid antagonist naltrexone has been forwarded as a medication that can forestall relapse and, in an extended-release formulation, has demonstrated some treatment success. However, chronic naltrexone treatment has not been extensively investigated in nonhuman subjects and aspects of its pharmacology remain uncertain. For example, the relative effectiveness of naltrexone in reducing the priming strength of opioid agonists differing in efficacy is not well understood. Here, using intravenous self-administration and warm-water tail withdrawal procedures, we investigated changes in the direct reinforcing effects of oxycodone and in the priming strength and antinociceptive effects of opioid agonists in squirrel monkeys (n = 4) during chronic treatment with naltrexone (0.2 mg/kg/d). Results show that naltrexone produced: 1) a 10-fold rightward shift in the dose-response function for the reinforcing effects of oxycodone, and 2) in reinstatement and antinociception experiments, comparable rightward shifts in the dose-response functions for higher-efficacy MOR agonists (methadone, heroin, and oxycodone) but rightward and downward shifts in the dose-response functions for lower-efficacy MOR agonists (buprenorphine, nalbuphine, and butorphanol). These results suggest that, although chronic naltrexone should be effective in forestalling relapse following exposure to lower- and higher-efficacy agonists, the inability of lower-efficacy agonists to surmount naltrexone antagonism may complicate the prescription of opioids for pain. SIGNIFICANCE STATEMENT: Although naltrexone is commonly used in the treatment of opioid use disorder, its ability to reduce the priming strength of opioid agonists has not been extensively investigated. This study shows that chronic naltrexone treatment induces rightward shifts in the reinstatement and antinociceptive properties of higher efficacy opioid agonists, but rightward and downward shifts for lower efficacy opioid agonists, suggesting lower efficacy agonists may not be able to surmount naltrexone-induced antagonism of these two effects, and perhaps naltrexone offers greater protection against lower efficacy agonists.

Two Weeks of Continuous Opioid Treatment in an Adenine-Induced Mouse Model of Chronic Kidney Disease Exacerbates the Bone Inflammatory State and Increases Osteoclasts.

Patients with chronic kidney disease (CKD) report high pain levels, but reduced renal clearance eliminates many analgesic options; therefore, 30-50% of CKD patients have chronic opioid prescriptions. Opioid use in CKD is associated with higher fracture rates. Opioids may directly alter bone turnover directly through effects on bone cells and indirectly via increasing inflammation. We hypothesized that continuous opioid exposure would exacerbate the high bone turnover state of CKD and be associated with elevated measures of inflammation. Male C57Bl/6J mice after 8 weeks of adenine-induced CKD (AD) and non-AD controls (CON) had 14-day osmotic pumps (0.25-µL/hr release) containing either saline or 50-mg/mL oxycodone (OXY) surgically implanted in the subscapular region. After 2 weeks, all AD mice had elevated blood urea nitrogen, parathyroid hormone, and serum markers of bone turnover compared to controls with no effect of OXY. Immunohistochemical staining of the distal femur showed increased numbers of osteocytes positive for the mu opioid and for toll-like receptor 4 (TLR4) due to OXY. Osteocyte protein expression of tumor necrosis factor-α (TNF-α) and RANKL were higher due to both AD and OXY so that AD + OXY mice had the highest values. Trabecular osteoclast-covered surfaces were also significantly higher due to both AD and OXY, resulting in AD + OXY mice having 4.5-fold higher osteoclast-covered surfaces than untreated CON. These data demonstrate that opioids are associated with a pro-inflammatory state in osteocytes which increases the pro-resorptive state of CKD.

Blocking IL-17A prevents oxycodone-induced depression-like effects and elevation of IL-6 levels in the ventral tegmental area and reduces oxycodone-derived physical dependence in rats.

Oxycodone is the most prescribed opioid for pain management and has been available in clinics for almost a century, but effects of chronic oxycodone have been studied less than morphine in preclinical and clinical studies. Newly developed depression has been coupled with chronic oxycodone use in a few clinical studies, but no preclinical studies have investigated the pathogenesis of oxycodone-induced depression. Gut microbiome changes following oxycodone use is an understudied area, and interleukin-17A (IL-17A) is linked to both the development of mood disorders and regulation of gut microbiome. The present study investigated effects of chronic oxycodone exposure on mood-related behaviors (depression and anxiety), pain hypersensitivity, physical dependence, immune markers, and the gut microbiome and tested the hypothesis that blocking IL-17A with a systemically administered monoclonal antibody reduces oxycodone-derived effects. Oxycodone (using an incremental dosing regimen) or saline was injected twice a day for 12 days. IL-17A Ab (200 µg/100 µl) or saline was administered every 3rd day during the 12-day interval. Chronic oxycodone induced a depression-like effect, but not anxiogenic- or anxiolytic-like effects; promoted hyperalgesia; increased IL-17A and IL-6 levels in the ventral tegmental area (VTA); and induced physical dependence. IL-17A Ab co-administration with oxycodone prevented the depression-like effect and hyperalgesia, reduced naloxone-precipitated withdrawal signs, and normalized the increase in cytokine levels. Chronic oxycodone exposure did not affect gut microbiome and integrity. Our results identify a role for IL-17A in oxycodone-related behavioral and neuroimmune effects and show that IL-17A Ab has potential therapeutic value in blocking these effects. Given that humanized IL-17A Ab is approved for treatment of psoriasis and psoriatic arthritis, our findings point toward studying it for use in the treatment of oxycodone use disorder.

Restrictive opioid prescribing after surgery for prolapse and incontinence: a randomized, noninferiority trial.

BACKGROUND: Opioids are routinely prescribed for postoperative pain control after gynecologic surgery with growing evidence showing that most prescribed opioids go unused. Restrictive opioid prescribing has been implemented in other surgical specialties to combat the risk for opioid misuse and diversion. The impact of this practice in the urogynecologic patient population is unknown. OBJECTIVE: This study aimed to determine if a restrictive opioid prescription protocol is noninferior to routine opioid prescribing in terms of patient satisfaction with pain control after minor and major surgeries for prolapse and incontinence. STUDY DESIGN: This was a single-center, randomized, noninferiority trial of opioid-naïve patients who underwent minor (eg, colporrhaphy or mid-urethral sling) or major (eg, vaginal or minimally invasive abdominal prolapse repair) urogynecologic surgery. Patients were excluded if they had contraindications to all multimodal analgesia and if they scored ≥30 on the Pain Catastrophizing Scale. Subjects were randomized on the day of surgery to the standard opioid prescription protocol (wherein patients routinely received an opioid prescription upon discharge [ie, 3-10 tablets of 5 mg oxycodone]) or to the restrictive protocol (no opioid prescription unless the patient requested one). All patients received multimodal pain medications. Participants and caregivers were not blinded. Subjects were asked to record their pain medication use and pain levels for 7 days. The primary outcome was satisfaction with pain control reported at the 6-week postoperative visit. We hypothesized that patient satisfaction with the restrictive protocol would be noninferior to those randomized to the standard protocol. The noninferiority margin was 15 percentage points. Pain level scores, opioid usage, opioid prescription refills, and healthcare use were secondary outcomes assessed for superiority. RESULTS: A total of 133 patients were randomized, and 127 (64 in the standard arm and 63 in the restrictive arm) completed the primary outcome evaluation and were included in the analysis. There were no statistically significant differences between the study groups, and this remained after adjusting for the surgery type. Major urogynecologic surgery was performed in 73.6% of the study population, and minor surgery was performed in 26.4% of the population. Same-day discharge occurred for 87.6% of all subjects. Patient satisfaction was 92.2% in the standard protocol arm and 92.1% in the restrictive protocol arm (difference, -0.1%; P=.004), which met the criterion for noninferiority. No opioid usage in the first 7 days after hospital discharge was reported by 48.4% of the patients in the standard protocol arm and by 70.8% in the restrictive protocol arm (P=.009). Opioid prescription refills occurred in 8.5% of patients with no difference between the study groups (9.4% in the standard arm vs 6.7% in the restrictive arm; P=.661). No difference was seen in the rate of telephone calls and urgent visits for pain control between the study arms. CONCLUSION: Among women who underwent minor and major surgery for prolapse and incontinence, patient satisfaction rates were noninferior after restrictive opioid prescribing when compared with routine opioid prescribing.

A personalized protocol for prescribing opioids after cesarean delivery: leveraging the electronic medical record to reduce outpatient opioid prescriptions.

BACKGROUND: Although cesarean delivery is the most common surgery performed in the United States, prescribing practices for analgesia vary. Strategies to manage postpartum pain have mostly focused on the immediate postpartum period when patients are still admitted to the hospital. At discharge, most providers prescribe a fixed number of opioid tablets. Most patients do not use all the opioids that they are prescribed at hospital discharge. This leads to an excess of opioids in the community, which can ultimately lead to misuse and diversion. OBJECTIVE: This study aimed to determine whether a transition from universal opioid prescribing to a personalized, patient-specific protocol decreases morphine milligram equivalents prescribed at hospital discharge after cesarean delivery while adequately controlling pain. STUDY DESIGN: This was a prospective cohort study of patients undergoing cesarean delivery before and after the implementation of a personalized opioid-prescribing practice at the time of hospital discharge. Each patient was prescribed scheduled ibuprofen and acetaminophen, with a prescription for oxycodone tablets equal to 5 times the morphine milligram equivalents used in the 24 hours before discharge, calculated via an electronic order set. The previous traditional cohorts were routinely prescribed 30 tablets of acetaminophen-codeine 300/30 mg. The primary outcome was morphine milligram equivalents prescribed at discharge. A hotline to address pain control issues after discharge was established, and calls, emergency department visits, and readmissions were examined. Statistical analyses was performed using chi-square and Wilcoxon rank-sum test, with a P value of <.05 considered statistically significant. RESULTS: Overall, 412 patients underwent cesarean delivery in the 6 weeks after initiation of the personalized prescribing protocol and were compared with 367 patients before the change. The median morphine milligram equivalents prescribed at discharge was lower with personalized prescribing (37.5 [interquartile range, 0-75] vs 135 [interquartile range, 135-135]; P<.001). Moreover, 176 patients (43%) were not prescribed opioids at discharge, which was a substantial change as all 367 patients in the traditional cohort received opioids at discharge (P<.001). Of note, 9 hotline phone calls were received; none required additional opioids after a 24-hour trial of scheduled ibuprofen, which none had taken before the call. In addition, 11 patients (2.7%) presented to the emergency department for pain evaluation, of which none required readmission or an outpatient prescription of opioids. CONCLUSION: A personalized protocol for opioid prescriptions after cesarean delivery decreased the total morphine milligram equivalents and the number of opioid tablets at discharge, without hospital readmissions or need for rescue opioid prescriptions after discharge. Opioids released into our community will be reduced by more than 90,000 tablets per year, without demonstrable adverse effect.

Breast milk oxycodone concentrations in mothers given oxycodone for post-Caesarean delivery pain management.

AIMS: Both effective analgesia and early breastfeeding play an important role in maternal and neonatal well-being after Caesarean delivery. We studied controlled-release oxycodone tablet treatment for postoperative pain management and determined the excretion of oxycodone into breast milk. METHODS: Controlled-release oxycodone/naloxone 10/5-mg tablets (n = 21) or controlled-release oxycodone 10-mg tablets (n = 22) were administered to mothers twice a day for the first 3 days after elective Caesarean delivery as a part of multimodal analgesia. Maternal plasma and breast milk samples were collected daily. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed with ultra-performance liquid chromatography-mass spectrometry. Maternal pain intensity was recorded with an 11-point Numeric Rating Scale (0-10). Neonatal oxycodone exposure was estimated by simulating five different exposure scenarios, including the highest possible exposure through breast milk. RESULTS: The mean oxycodone and noroxycodone milk-to-maternal plasma ratios were 3.2 and 3.0, respectively. A strong correlation was found between plasma and breast milk oxycodone (R2 = 0.87) and noroxycodone concentrations (R2 = 0.91). In the simulated highest neonatal exposure scenario, the neonate's maximum plasma concentration was estimated to be 5.4 ng/mL and the estimated weight-adjusted infant oxycodone dose was less than 10% of the maternal dose. Pain intensities were similarly low between the two treatment groups. CONCLUSIONS: The oxycodone dose received from colostrum and breast milk during the first three postoperative days after Caesarean delivery is assumed safe for healthy, term neonates, but in extreme cases it is possible for the neonate to receive a dose through breast milk that may elicit opioid effects.

Oxycodone initiation in Australia (2014-2018): Sociodemographic factors and preceding health service use.

AIMS: Oxycodone is the most commonly prescribed strong opioid in Australia. This study describes health service antecedents and sociodemographic factors associated with oxycodone initiation. METHODS: Population-based new user cohort study linking medicine dispensings, hospitalizations, emergency department visits, medical services and cancer notifications from New South Wales (NSW) for 2014-2018. New users had no dispensings of any opioid in the preceding year. We analysed health service use in the 5 days preceding initiation and proportion of people on treatment over 1 year and fitted an area-based, multivariable initiation model with sociodemographic covariates. RESULTS: Oxycodone accounted for 30% of opioid initiations. Annually, 3% of the NSW population initiated oxycodone, and 5-6% were prevalent users; the new user cohort comprised 830 963 people. Discharge from hospital (39.3%), therapeutic procedures (21.4%) and emergency department visits (19.7%) were common; a hospital admission for injury (6.0%) or a past-year history of cancer (7.2%) were less common. At 1 year after initiation, 4.6% of people were using oxycodone. In the multivariable model, new use of oxycodone increased with age and was higher for people outside major cities, for example, an incidence rate ratio of 1.43 (95% confidence interval 1.36-1.51) for inner regional areas relative to major cities; there was no evidence of variation in rates of new use by social disadvantage. CONCLUSION: About half of new oxycodone use in NSW was preceded by a recent episode of hospital care or a therapeutic procedure. Higher rates of oxycodone initiation in rural and regional areas were not explained by sociodemographic factors.

Comparing withdrawal- and anxiety-like behaviors following oral and subcutaneous oxycodone administration in C57BL/6 mice.

Excessive prescribing and misuse of prescription opioids, such as oxycodone, significantly contributed to the current opioid crisis. Although oxycodone is typically consumed orally by humans, parenteral routes of administration have primarily been used in preclinical models of oxycodone dependence. To address this issue, more recent studies have used oral self-administration procedures to study oxycodone seeking and withdrawal in rodents. Behavioral differences, however, following oral oxycodone intake versus parenteral oxycodone administration remain unclear. Thus, the goal of the current studies was to compare anxiety- and withdrawal-like behaviors using established opioid dependence models of either home cage oral intake of oxycodone (0.5 mg/ml) or repeated subcutaneous (s.c.) injections of oxycodone (10 mg/kg) in male and female mice. Here, mice received 10 days of oral or s.c. oxycodone administration, and following 72 h of forced abstinence, anxiety- and withdrawal-like behaviors were measured using elevated zero maze, open field, and naloxone-induced precipitated withdrawal procedures. Global withdrawal scores were increased to a similar degree following oral and s.c. oxycodone use, while both routes of oxycodone administration had minimal effects on anxiety-like behaviors. When examining individual withdrawal-like behaviors, mice receiving s.c. oxycodone exhibited more paw tremors and jumps during naloxone-induced precipitated withdrawal compared with oral oxycodone mice. These results indicate that both models of oxycodone administration are sufficient to elevate global withdrawal scores, but, when compared with oral consumption, s.c. oxycodone injections yielded more pronounced effects on some withdrawal-like behaviors.

Drug-drug interaction perpetrators of oxycodone in patients with cancer: frequency and clinical relevance.

AIM: Oxycodone is known to have numerous drug-drug interactions (DDIs) that can potentially decrease efficacy or lead to adverse drug reactions (ADRs). However, there is limited research on the frequency of DDIs associated with oxycodone, which is important in optimising pharmacovigilance and the need for additional research on certain DDIs. In this study, the frequency of pharmacologically and clinically relevant DDI perpetrators was studied in patients with cancer. METHODS: This was a cross-sectional study using hospital pharmacy records of patients with cancer who were prescribed oxycodone between September 2021 and September 2022. Medication records of patients prescribed oxycodone during a period of ≥ 5 consecutive days (= oxycodone treatment episodes) were reviewed to identify the concomitant use of pharmacologically relevant perpetrators, based on reference sources (Lexicomp®, Micromedex®, the Dutch Kennisbank and the Dutch Commentaren Medicatiebewaking). The clinical relevance was examined by a clinical pharmacologist and a medical oncologist. Additionally, the frequency of double interactions-concomitant oxycodone use with two CYP3A4 and / or CYP2D6 perpetrators-was studied. RESULTS: Overall, 254 oxycodone treatment episodes were included, of which 227 (89.4%) were found to contain at least one pharmacologically relevant DDI perpetrator. Of these, 210 (82.7%) were considered to be clinically relevant. A total of 80 different pharmacologically relevant perpetrators were identified, with 65 (81.3%) being considered clinically relevant. Double interactions were observed in 21 (8.3%) oxycodone treatment episodes. CONCLUSION: A high frequency of pharmacologically and clinically relevant perpetrators of oxycodone was observed in our cohort. Moreover, a high number of double interactions involving oxycodone was registered. More intense monitoring of DDIs may be needed to improve medication safety of patients with cancer taking oxycodone.

The effect of opioid use on traffic fatalities.

We use a difference-in-differences design to study the effect of opioid use on traffic fatalities. Following Alpert et al., we focus on the 1996 introduction and marketing of OxyContin, and we examine its long-term impacts on traffic fatalities involving Schedule II drugs or heroin. Based on the national fatal vehicle crash database, we find that the states heavily targeted by the initial marketing of OxyContin (i.e., non-triplicate states) experienced 2.4 times more traffic fatalities (1.6 additional deaths per million individuals) involving Schedule II drugs or heroin during 2011-2019, when overdose deaths from heroin and fentanyl became more prominent. We find no difference in traffic fatalities until after the mid-2000s between states with and without a triplicate prescription program. The effect is mainly concentrated in fatal crashes with drug involvement of drivers ages between 25 and 44. Our results highlight additional long-term detrimental consequences of the introduction and marketing of OxyContin.

The impact of more restrictive hydrocodone rescheduling on unintentional pediatric opioid exposures.

PURPOSE: To evaluate the impact of rescheduling hydrocodone combination products (HCPs) from schedule III of the Controlled Substances Act to the more restrictive schedule II on unintentional pediatric exposures (≤5 years old). METHODS: Using U.S. data on outpatient retail pharmacy dispensing, emergency department (ED) visits, and poison center (PC) exposure cases, we assessed trends in prescriptions dispensed and unintentional pediatric exposure cases involving hydrocodone (rescheduled from III to II) compared to oxycodone (schedule II) and codeine (schedule III for combination products) using descriptive and interrupted time-series (ITS) analyses during the 16 quarters before and after the October 2014 rescheduling of HCPs. RESULTS: Dispensing of hydrocodone products was declining before rescheduling but declined more steeply post-rescheduling. In ITS analyses, both hydrocodone and oxycodone had significant slope decreases in PC case rates in the post versus pre-period that was larger for hydrocodone, while codeine had a small but significant slope increase in PC case rates. An estimated 4202 ED visits for pediatric hydrocodone exposures occurred in the pre-period and 2090 visits occurred in the post-period, a significant decrease of 50.3%. Oxycodone exposures showed no significant decrease. CONCLUSIONS: Pediatric hydrocodone unintentional exposure ED visits and PC cases decreased after HCP rescheduling more than would be expected had the pre-rescheduling trend continued; the acceleration in the decrease in hydrocodone PC cases was partially offset by a slowing in the decrease in codeine-involved cases. The trend changes were likely due to multiple factors, including changes in dispensing that followed the rescheduling. Unintentional pediatric medication exposures and poisonings remain a public health concern requiring ongoing, multifaceted mitigation efforts.

Opioid therapy trajectories of patients with chronic non-cancer pain over 1 year of follow-up after initiation of short-acting opioid formulations.

OBJECTIVE: This study compared opioid utilization trajectories of persons initiating tramadol, short-acting hydrocodone, or short-acting oxycodone, and it characterized opioid dose trajectories and type of opioid in persistent opioid therapy subsamples. METHODS: A retrospective cohort study of adults with chronic non-cancer pain who were initiating opioid therapy was conducted with the IQVIA PharMetrics® Plus for Academics data (2008-2018). Continuous enrollment was required for 6 months before ("baseline") and 12 months after ("follow-up") the first opioid prescription ("index date"). Opioid therapy measures were assessed every 7 days over follow-up. Group-based trajectory modeling (GBTM) was used to identify trajectories for any opioid and total morphine milligram equivalent measures, and longitudinal latent class analysis was used for opioid therapy type. RESULTS: A total of 40 276 tramadol, 141 023 hydrocodone, and 45 221 oxycodone initiators were included. GBTM on any opioid therapy identified 3 latent trajectories: early discontinuers (tramadol 39.0%, hydrocodone 54.1%, oxycodone 61.4%), late discontinuers (tramadol 37.9%, hydrocodone 39.4%, oxycodone 33.3%), and persistent therapy (tramadol 6.7%, hydrocodone 6.5%, oxycodone 5.3%). An additional fourth trajectory, intermittent therapy (tramadol 16.4%), was identified for tramadol initiators. Of those on persistent therapy, 2687 individuals were on persistent therapy with tramadol, 9169 with hydrocodone, and 2377 with oxycodone. GBTM on opioid dose resulted in 6 similar trajectory groups in each persistent therapy group. Longitudinal latent class analysis on opioid therapy type identified 6 latent classes for tramadol and oxycodone and 7 classes for hydrocodone. CONCLUSION: Opioid therapy patterns meaningfully differed by the initial opioid prescribed, notably the presence of intermittent therapy among tramadol initiators and higher morphine milligram equivalents and prescribing of long-acting opioids among oxycodone initiators.

An ultrasound-guided serratus anterior plane block with continuous local anaesthetic infusion and epidural analgesia for rib fracture pain.

BACKGROUND: We compared analgesia with an ultrasound (US)-guided serratus anterior plane block (SAPB) to thoracic epidural analgesia (EA) with continuous local anaesthetic infusion in patients with unilateral multiple traumatic rib fractures. EA often carries contraindications in patients with multiple rib fractures (MRFs), whereby having alternative effective methods to treat rib fracture pain remains important to patient care. Thus, we hypothesised that both regional anaesthetic techniques would provide effective pain relief. METHODS: In this study, we included 59 patients with unilateral MRFs and a numerical rating scale (NRS) pain score ≥4 at rest or upon movement. Patients were randomised to receive a US-guided SAPB or continuous infusion EA with 2 mg/mL ropivacaine. Patients were given a patient-controlled analgesia (PCA) device with intravenous oxycodone boluses for rescue medication. The primary outcome was a change in the NRS score at rest and upon movement from baseline to Day 2 following the block. We also measured the forced expiratory volume in 1 s of expiration (FEV1) and FEV1% at the same time points when NRS was measured. The total consumption of oxycodone with PCA was measured at 24 and 48 h after the block. RESULTS: We detected a significant reduction (≥2) in NRS for both groups; however, EA associated with a greater reduction in NRS upon movement after block initiation. The mean reduction in NRS upon movement within 1 h was 3 (1.8, p < .01) in the SAPB group versus 4.7 (2.4, p < .01) in the EA group. We found no significant difference between groups in pain scores on Days 1 and 2 following the block. In the EA group, FEV1% increase in the first 12 h from baseline. Finally, PCA oxycodone consumption did not differ between groups. CONCLUSIONS: SAPB with continuous local anaesthetic infusion is an effective alternative to treat rib fracture pain when EA is contraindicated. We found that SABP significantly reduces pain in patients with unilateral MRFs, although EA achieves better analgesia over the first 12 h following the block.

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.

Efficacy of postoperative analgesia with intravenous paracetamol and mannitol injection, combined with thoracic paravertebral nerve block in post video-assisted thoracoscopic surgery pain: a prospective, randomized, double-blind controlled trial.

BACKGROUND: Although video-assisted thoracoscopic surgery (VATS) has advantages of reduced injury and faster healing, patients still endure moderate and severe postoperative pain. Paracetamol and mannitol injection, the first acetaminophen injection in China, has the advantages of convenient administration, rapid onset of action, and no first-pass effect. This aim of this study was to investigate the efficacy of postoperative analgesia with paracetamol and mannitol injection, combined with thoracic paravertebral nerve block (TPVB) in post VATS pain. METHODS: This study was a single-center, prospective, randomized, double-blind controlled clinical trial. Patients scheduled for VATS were randomly divided into three groups, general anesthesia group (Group C), TPVB group (Group T) and TPVB + paracetamol and mannitol injection group (Group TP). In this study, the primary outcome was determined as visual analog scale (VAS) scores at rest and coughing, the secondary observation outcomes were the first time to use analgesic pump, the total consumption of oxycodone in the analgesic pump, number of effective and total analgesic pump compressions at first 48 h postoperatively, the perioperative consumption of sufentanil, time to extubation, hospital length of stay, urine volume, and the incidence of adverse events. RESULTS: In a state of rest and cough, patients in the Group TP showed significantly lower VAS pain scores at 1, 12, 24, and 48 postoperative-hour compared with Group C and Group T. Intraoperative sufentanil and postoperative oxycodone consumption, the first time to press analgesic pump, the times of effective and total compressions of patient- controlled analgesia (PCA) were lower than those of the Group C and Group T. Interestingly, urine output was higher in Group TP. There were no differences between the three groups in terms of extubation time, length of hospital stay and adverse effects, indicating that intravenous paracetamol and mannitol injection is an effective and safe perioperative analgesia method. CONCLUSIONS: Paracetamol and mannitol injection, combined with TPVB may provide important beneficial effects on acute pain control and reduce the consumption of opioid in patients undergoing VATS. TRIAL REGISTRATION: The trial was registered on Jun 19, 2023 in the Chinese Clinical Trial Registry ( https://www.chictr.org.cn/showproj.html?proj=199315 ), registration number ChiCTR2300072623 (19/06/2023).

Analgesic effect of the ultrasound-guided thoracolumbar paravertebral block in patients undergoing robot-assisted laparoscopic nephrectomy: a randomized controlled trial.

BACKGROUND: Paravertebral block has similar effect as epidural anesthesia, and has good somatic and visceral analgesic effect. Paravertebral block is widely used in thoracic surgery, but rarely used in abdominal surgery. AIMS: This study aimed to evaluate the analgesic effect of thoracolumbar paravertebral block in patients undergoing robot-assisted laparoscopic nephrectomy. METHODS: One hundred patients undergoing elective robot-assisted laparoscopic nephrectomy were included in this study. Based on whether the thoracolumbar paravertebral block was performed, the patients were randomly divided into the thoracolumbar paravertebral block combined with general anesthesia group (TL-PVB group) and simple general anesthesia group (NO-PVB group). Oxycodone was administered for patient-controlled intravenous analgesia (PCIA). The primary outcomes included the amount of remifentanil used during surgery, the amount of oxycodone used in 24 and 48 h after surgery. Secondary outcomes included the changes of heart rate (HR) and mean arterial pressure (MAP), time for the first analgesia administration, visual analog score (VAS) of pain during rest and movement, and time of postoperative recovery. RESULTS: Compared to the NO-PVB group, the amount of remifentanil used during surgery in patients with TL-PVB group was significantly reduced (1.78 ± 0.37 mg vs. 3.09 ± 0.48 mg, p < 0.001), the amount of oxycodone used 24 h after surgery was significantly reduced (8.70 ± 1.70 mg vs. 13.79 ± 2.74 mg, p < 0.001), and the amount of oxycodone used 48 h after surgery was remarkably reduced (21.83 ± 4.28 mg vs. 27.27 ± 4.76 mg, p < 0.001). There were significant differences in the changes of HR and MAP between the two groups (p < 0.001). The first analgesic requirement time of TL-PVB group was significantly longer than that of NO-PVB group (468.56 ± 169.60 min vs. 113.48 ± 37.26 min, p < 0.001). The postoperative VAS during rest and movement of TL-PVB group were significantly lower than that of NO-PVB group (p < 0.01). Compared with NO-PVB group, patients in TL-PVB group needed shorter time to awaken from anesthesia, leave the operating room, anal exhaust, get out of bed, and had shorter length of postoperative hospital stay (p < 0.001). The incidence of postoperative adverse reactions were lower in the TL-PVB group than that in the NO-PVB group (p < 0.05). CONCLUSIONS: Ultrasound-guided thoracolumbar paravertebral block significantly reduces intraoperative and postoperative opioid consumption, and provides better analgesia in patients undergoing robot-assisted laparoscopic nephrectomy, which is a recommendable combined anesthesia technique. TRIAL REGISTRATION: ChiCTR2200061326, 21/06/2022.

Orbitofrontal cortex and dorsal striatum functional connectivity predicts incubation of opioid craving after voluntary abstinence.

We recently introduced a rat model of incubation of opioid craving after voluntary abstinence induced by negative consequences of drug seeking. Here, we used resting-state functional MRI to determine whether longitudinal functional connectivity changes in orbitofrontal cortex (OFC) circuits predict incubation of opioid craving after voluntary abstinence. We trained rats to self-administer for 14 d either intravenous oxycodone or palatable food. After 3 d, we introduced an electric barrier for 12 d that caused cessation of reward self-administration. We tested the rats for oxycodone or food seeking under extinction conditions immediately after self-administration training (early abstinence) and after electric barrier exposure (late abstinence). We imaged their brains before self-administration and during early and late abstinence. We analyzed changes in OFC functional connectivity induced by reward self-administration and electric barrier-induced abstinence. Oxycodone seeking was greater during late than early abstinence (incubation of oxycodone craving). Oxycodone self-administration experience increased OFC functional connectivity with dorsal striatum and related circuits that was positively correlated with incubated oxycodone seeking. In contrast, electric barrier-induced abstinence decreased OFC functional connectivity with dorsal striatum and related circuits that was negatively correlated with incubated oxycodone seeking. Food seeking was greater during early than late abstinence (abatement of food craving). Food self-administration experience and electric barrier-induced abstinence decreased or maintained functional connectivity in these circuits that were not correlated with abated food seeking. Opposing functional connectivity changes in OFC with dorsal striatum and related circuits induced by opioid self-administration versus voluntary abstinence predicted individual differences in incubation of opioid craving.

A rapid and sensitive LC-MS/MS method for quantifying oxycodone, noroxycodone, oxymorphone and noroxymorphone in human plasma to support pharmacokinetic drug interaction studies of oxycodone.

A sensitive and reliable LC-MS/MS method was developed and validated for the quantification of oxycodone and metabolites in human plasma. The method has a runtime of 6 min and a sensitivity of 0.1 µg/L for all analytes. Sample preparation consisted of protein precipitation. Separation was performed on a Kinetix biphenyl column (2.1 × 100 mm, 1.7 µm), using ammonium formate 5 mm in 0.1% aqueous formic acid and methanol LC-MS grade 100% in gradient elution at a flow rate of 0.4 ml/min. Detection was performed in multiple reaction monitoring mode using positive electrospray ionization. The method was linear over the calibration range of 0.1-25.0 µg/L for oxycodone, noroxycodone and noroxymorphone and 0.1-5.0 µg/L for oxymorphone. The method demonstrated good performance in terms of intra- and interday accuracy (86.5-110.3%) and precision (CV 1.7-9.3%). The criteria for the matrix effect were met (CV < 15%) except for noroxymorphone, for which an additional method was applied to compensate for the matrix effect. Whole blood samples were stable for 4 h at room temperature. Plasma samples were stable for 24 h at room temperature and 3 months at -20°C. Furthermore, the method was successfully applied in a pharmacokinetic drug interaction study of oxycodone and enzalutamide in patients with prostate cancer.