Tramadol-paracetamol for postoperative pain after spine surgery - A randomized, double-blind, placebo-controlled study.

OBJECTIVES: Multimodal pain management is one component in enhanced recovery after surgery protocol. Here we evaluate the efficacy of tramadol-paracetamol in acute postoperative pain and pain outcome at 12 months after spine surgery in randomized, double-blind, placebo-controlled trial. METHODS: We randomized 120 patients undergoing spine surgery to receive, for add-on pain management, two tramadol-paracetamol 37.5 mg/325 mg (n = 61) or placebo tablets (n = 59) twice a day for 5 postoperative days. In the hospital, multimodal pain management consisted of dexketoprofen and oxycodone. After discharge, patients were prescribed ibuprofen 200 mg, maximum 1,200 mg/day. Pain, analgesic use, and satisfaction with pain medication were followed up with the Brief Pain Inventory questionnaire before surgery and at 1 and 52 weeks after surgery. The primary outcome was patients' satisfaction with pain medication 1 week after surgery. RESULTS: At 1 week after surgery, patients' satisfaction with pain medication was similarly high in the two groups, 75% [interquartile range, 30%] in the placebo group and 70% [40%] in the tramadol-paracetamol group (p = 0.949) on a scale: 0% = not satisfied, 100% = totally satisfied. At 1 week, ibuprofen dose was lower in the placebo group 200 mg [1,000] compared to the tramadol-paracetamol group, 800 mg [1,600] (p = 0.016). There was no difference in the need for rescue oxycodone. Patients in the tramadol-paracetamol group had more adverse events associated with analgesics during the first postoperative week (relative risk = 1.8, 95% confidence interval, 1.2-2.6). CONCLUSION: Add-on pain treatment with tramadol-paracetamol did not enhance patients' satisfaction with early pain management after back surgery.

Paradoxical potentiation of the exercise pressor reflex by endomorphin 2 in the presence of naloxone.

When contracting muscles are freely perfused, the acid-sensing ion channel 3 (ASIC3) on group IV afferents plays a minor role in evoking the exercise pressor reflex. We recently showed in isolated dorsal root ganglion neurons innervating the gastrocnemius muscles that two mu opioid receptor agonists, namely endomorphin 2 and oxycodone, potentiated the sustained inward ASIC3 current evoked by acidic solutions. This in vitro finding prompted us to determine whether endomorphin 2 and oxycodone, when infused into the arterial supply of freely perfused contracting hindlimb muscles, potentiated the exercise pressor reflex. We found that infusion of endomorphin 2 and naloxone in decerebrated rats potentiated the pressor responses to contraction of the triceps surae muscles. The endomorphin 2-induced potentiation of the pressor responses to contraction was prevented by infusion of APETx2, an ASIC3 antagonist. Specifically, the peak pressor response to contraction averaged 19.3 ± 5.6 mmHg for control (n = 10), 27.2 ± 8.1 mmHg after naloxone and endomorphin 2 infusion (n = 10), and 20 ± 8 mmHg after APETx2 and endomorphin 2 infusion (n = 10). Infusion of endomorphin 2 and naloxone did not potentiate the pressor responses to contraction in ASIC3 knockout rats (n = 6). Partly similar findings were observed when oxycodone was substituted for endomorphin 2. Oxycodone infusion significantly increased the exercise pressor reflex over its control level, but subsequent APETx2 infusion failed to restore the increase to its control level (n = 9). The peak pressor response averaged 23.1 ± 8.6 mmHg for control (n = 9), 33.2 ± 11 mmHg after naloxone and oxycodone were infused (n = 9), and 27 ± 8.6 mmHg after APETx2 and oxycodone were infused (n = 9). Our data suggest that after opioid receptor blockade, ASIC3 stimulation by the endogenous mu opioid, endomorphin 2, potentiated the exercise pressor reflex.NEW & NOTEWORTHY This paper provides the first in vivo evidence that endomorphin 2, an endogenous opioid peptide, can paradoxically increase the magnitude of the exercise pressor reflex by an ASIC3-dependent mechanism even when the contracting muscles are freely perfused.

Oxycodone does not affect placental circulatory physiology during the early first stage of labor-A randomized trial.

INTRODUCTION: Opioids are used for pain relief during the first stage of labor. Oxycodone can cause maternal hypotension that may modify utero- and fetoplacental circulatory physiology. We hypothesized that maternal intravenous (i.v.) oxycodone has no detrimental effect on utero- and fetoplacental hemodynamics during the early first stage of labor. MATERIAL AND METHODS: Twenty-two parturients requiring pain relief during the first stage of labor were randomized in a double-blinded and placebo-controlled study. By Doppler ultrasonography, both uterine artery (Ut) and umbilical vein (UV) volume blood flows (Q), Ut pulsatility index (PI), and Ut vascular resistance (RUt) were calculated. Blood flow velocity waveforms were obtained between uterine contractions. After baseline measurements, women received oxycodone 0.05 mg/kg or a placebo intravenous. Doppler ultrasonography was repeated up to 120 min after the first drug administration. The second dose of oxycodone 0.05 mg/kg was allowed at 60 min to all parturients with contraction pain ≥5/10. Maternal plasma samples were collected at each study phase and after delivery with umbilical cord plasma samples, to measure oxycodone concentrations. CLINICALTRIALS: gov identifier (NCT no. NCT02573831). RESULTS: At baseline, mean QUt and QUV did not differ significantly between the placebo-first (478 mL/min and 57 mL/min/kg) and the oxycodone-first (561 mL/min and 71 mL/min/kg) groups. In addition, RUt and Ut PI were comparable between the groups. Following oxycodone at 60 min, mean QUt and QUV (714 mL/min and 52 mL/min/kg) were similar to the placebo-first (520 mL/min and 55 mL/min/kg) group. Furthermore, all the measured parameters were comparable to the baseline values. At 60 min after the first study drug administration, all the parturients in the placebo-first group needed intravenous oxycodone 0.05 mg/kg. At 120 min, we found no statistically significant change in any of the measured parameters. No significant correlation was found between maternal oxycodone concentration and QUt or QUV. Furthermore, newborn oxycodone concentration did not correlate with QUV. CONCLUSIONS: Oxycodone did not have any detrimental effect on either utero- or fetoplacental circulatory physiology during the early first stage of labor. Maternal plasma oxycodone did not correlate with utero- and fetoplacental hemodynamics. No correlation was found between newborn oxycodone concentration and fetoplacental hemodynamics.

Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys.

Recent studies suggest that dopamine D3 receptors (D3R) may be a therapeutic target for opioid use disorders (OUD). This study examined the effects of the D3R partial agonist (±)VK4-40 and the D3R-selective antagonist (±)VK4-116, compared to the mu-opioid receptor antagonist naltrexone (NTX), in nonhuman primate models of OUD and antinociception. Adult male and female (N = 4/sex) cynomolgus monkeys were trained to self-administer oxycodone (0.003-0.1 mg/kg/injection) first under a fixed-ratio (FR) and then a progressive-ratio (PR) schedule of reinforcement during daily 1- and 4-hr sessions, respectively. Under the FR schedule, intravenous NTX (0.01-0.1 mg/kg), (±)VK4-116 (1.0-10 mg/kg), and (±)VK4-40 (1.0-10 mg/kg) were studied in combination with the peak oxycodone dose and a dose on the descending limb of the dose-effect curve; NTX and (±)VK4-40 were also studied at the peak of the PR dose-response curve (N = 4). Following saline extinction, each compound was examined on oxycodone-induced reinstatement. Finally, these compounds were assessed in adult male rhesus monkeys (N = 3) in a warm-water (38 °C, 50 °C, 54 °C) tail withdrawal assay. NTX decreased responding on the peak of the FR oxycodone dose-response curve, but increased responding on the descending limb. (±)VK4-40, but not (±)VK4-116, significantly decreased peak oxycodone self-administration; (±)VK4-40 did not increase responding on the descending limb. NTX and (±)VK4-40, but not (±)VK4-116, attenuated oxycodone-induced reinstatement. Under PR responding, NTX and (±)VK4-40 decreased breakpoints. Oxycodone-induced antinociception was attenuated by NTX, but not by (±)VK4-40 or (±)VK4-116. Together, these results suggest that further research evaluating the effects of (±)VK4-40 as a novel pharmacotherapy for OUD is warranted.

The Role of Pharmacogenomics in Opioid Prescribing.

OPINION STATEMENT: Pharmacogenomics is increasingly important to guide objective, safe, and effective individualised prescribing. Personalised prescribing has revolutionised treatments in the past decade, allowing clinicians to maximise drug efficacy and minimise adverse effects based on a person's genetic profile. Opioids, the gold standard for cancer pain relief, are among the commonest medications prescribed in palliative care practice. This narrative review examines the literature surrounding opioid pharmacogenomics and its applicability to the palliative care cancer population. There is currently limited intersection between the fields of palliative care and pharmacogenomics, but growing evidence presents a need to build linkages between the two disciplines. Pharmacogenomic evidence guiding opioid prescribing is currently available for codeine and tramadol, which relates to CYP2D6 gene variants. However, these medications are prescribed less commonly for pain in palliative care. Research is accelerating with other opioids, where oxycodone (CYP2D6) and methadone (CYP2B6, ABCB1) already have moderate evidence of an association in terms of drug metabolism and downstream analgesic response and side effects. OPRM1 and COMT are receiving increasing attention and have implications for all opioids, with changes in opioid dosage requirements observed but they have not yet been studied widely enough to be considered clinically actionable. Current evidence indicates that incorporation of pharmacogenomic testing into opioid prescribing practice should focus on the CYP2D6 gene and its actionable variants. Although opioid pharmacogenomic tests are not widely used in clinical practice, the progressively reducing costs and rapid turnover means greater accessibility and affordability to patients, and thus, clinicians will be increasingly asked to provide guidance in this area. The upsurge in pharmacogenomic research will likely discover more actionable gene variants to expand international guidelines to impact opioid prescribing. This rapidly expanding area requires consideration and monitoring by clinicians in order for key findings with clinical implications to be accessible, meaningfully interpretable and communicated.

Leftover Opioid Analgesics and Disposal Following Ambulatory Pediatric Surgeries in the Context of a Restrictive Opioid-Prescribing Policy.

BACKGROUND: Opioid analgesics are commonly prescribed for postoperative analgesia following pediatric surgery and often result in leftover opioid analgesics in the home. To reduce the volume of leftover opioids and overall community opioid burden, the State of Tennessee enacted a policy to reduce initial opioid prescribing to a 3-day supply for most acute pain incidents. We aimed to evaluate the extent of leftover opioid analgesics following pediatric ambulatory surgeries in the context of a state-mandated restrictive opioid-prescribing policy. We also aimed to evaluate opioid disposal rates, methods of disposal, and reasons for nondisposal. METHODS: Study personnel contacted the parents of 300 pediatric patients discharged with an opioid prescription following pediatric ambulatory surgery. Parents completed a retrospective telephone survey regarding opioid use and disposal. Data from the survey were combined with data from the medical record to evaluate proportion of opioid doses prescribed that were left over. RESULTS: The final analyzable sample of 185 patients (62% response rate) were prescribed a median of 12 opioid doses (interquartile range [IQR], 12-18), consumed 2 opioid doses (IQR, 0-4), and had 10 opioid doses left over (IQR, 7-13). Over 90% (n = 170 of 185) of parents reported they had leftover opioid analgesics, with 83% of prescribed doses left over. A significant proportion (29%, n = 54 of 185) of parents administered no prescribed opioids after surgery. Less than half (42%, n = 71 of 170) of parents disposed of the leftover opioid medication, most commonly by flushing down the toilet, pouring down the sink, or throwing in the garbage. Parents retaining leftover opioids (53%, n = 90 of 170) were most likely to keep them in an unlocked location (68%, n = 61 of 90). Parents described forgetfulness and worry that their child will experience pain in the future as primary reasons for not disposing of the leftover opioid medication. CONCLUSIONS: Despite Tennessee's policy aimed at reducing leftover opioids, a significant proportion of prescribed opioids were left over following pediatric ambulatory surgeries. A majority of parents did not engage in safe opioid disposal practices. Given the safety risks related to leftover opioids in the home, further interventions to improve disposal rates and tailor opioid prescribing are warranted after pediatric surgery.

A limited access oral oxycodone paradigm produces physical dependence and mesocorticolimbic region-dependent increases in DeltaFosB expression without preference.

The abuse of oral formulations of prescription opioids has precipitated the current opioid epidemic. We developed an oral oxycodone consumption model consisting of a limited access (4 h) two-bottle choice drinking in the dark (TBC-DID) paradigm and quantified dependence with naloxone challenge using mice of both sexes. We also assessed neurobiological correlates of withdrawal and dependence elicited via oral oxycodone consumption using immunohistochemistry for DeltaFosB (ΔFosB), a transcription factor described as a molecular marker for drug addiction. Neither sex developed a preference for the oxycodone bottle, irrespective of oxycodone concentration, bottle position or prior water restriction. Mice that volitionally consumed oxycodone exhibited hyperlocomotion in an open field test and supraspinal but not spinally-mediated antinociception. Both sexes also developed robust, dose-dependent levels of opioid withdrawal that was precipitated by the opioid antagonist naloxone. Oral oxycodone consumption followed by naloxone challenge led to mesocorticolimbic region-dependent increases in the number of ΔFosB expressing cells. Naloxone-precipitated withdrawal jumps, but not the oxycodone bottle % preference, was positively correlated with the number of ΔFosB expressing cells specifically in the nucleus accumbens shell. Thus, limited access oral consumption of oxycodone produced physical dependence and increased ΔFosB expression despite the absence of opioid preference. Our TBC-DID paradigm allows for the study of oral opioid consumption in a simple, high-throughput manner and elucidates the underlying neurobiological substrates that accompany opioid-induced physical dependence.

Opiate vs non-opiate prescription medication for pain control after endoscopic sinus surgery for chronic rhinosinusitis.

PURPOSE: Research indicates that most providers give opiates after endoscopic sinonasal surgery. The effectiveness of non-opiate medications after sinonasal surgery is poorly understood and most studies do not assess medication failure. This study compares oral opiate, oral opiate and topical steroid, and oral non-opiate pain control. Patient call-backs are used as a proxy for pain medication failure. MATERIALS AND METHODS: This study compares three medication regiments after sinonasal surgery for 180 adults with chronic rhinosinusitis. Patients were instructed to take acetaminophen for mild pain. For moderate/severe pain, patients used: 1) oxycodone-acetaminophen, 2) oxycodone-acetaminophen + budesonide nasal rinses, or 3) meloxicam + acetaminophen. Patients were instructed to call clinic if pain was not controlled. Descriptive statistics compared cohorts. Chi-square tests compared call-backs between cohorts. Logistic regression adjusted for baseline differences in covariates, comorbidities, and operative sites. RESULTS: Cohorts had similar age, sex distribution, disease features, and extent of surgery. The meloxicam cohort had less subjects with pain disorders. The oxycodone cohort had less subjects with diabetes, septoplasty, and turbinate reduction. After adjusting for baseline differences and using oxycodone as the reference group (n = 50), the odds of calling clinic for poorly controlled pain was 0.18 (95% Confidence Interval (CI): 0.05-0.6) in the meloxicam cohort (n = 45) and 0.19 (95% CI:0.07-0.5) in the oxycodone + budesonide rinses cohort (n = 85). CONCLUSION: In this study, both meloxicam and oxycodone + budesonide rinses were more effective at controlling pain after sinonasal surgery than oxycodone alone.

Elevated customary alcohol consumption attenuates opioid effects.

BACKGROUND: Regular alcohol consumption is on the rise among older adults and has the potential of altering the subjective experience of pain and response to pain medications. This study examined the cognitive, analgesic and side effect response to oxycodone in middle age and older adults with elevated levels of customary alcohol consumption in a human laboratory setting. METHODS: After refraining from alcohol for one day, eligible participants underwent baseline assessment cognition and side effects by means of questionnaires that were repeated at three time points (90 min, 5 and 8 h) following administration of a 10 mg oral dose of oxycodone. Response to pain stimulus (Cold Pressor Test (CPT)), pupil size, and plasma oxycodone were also measured. RESULTS: One hundred twenty-eight adults (age 35-85) completed the study day. Compared to those with lower customary alcohol consumption, participants with elevated alcohol consumption showed attenuated opioid-induced pupil constriction and cognitive decline on objective measures of working memory, sustained attention, inhibitory control, coordination on a simulated driving task, and subjective dysphoric effects with enhanced subjective euphoric effects. Oxycodone pharmacokinetics, pain tolerance to CPT, and Berg balance were impacted comparably between alcohol consumption groups. Women endorsed greater negative drug effects, whereas men endorsed positive drug effects. CONCLUSION: Independent of subject's age, elevated customary alcohol consumption attenuates opioid central effects (i.e., pupil miosis, impaired cognition) and gender influences subjective drug effects. Clinicians should consider alcohol consumption and gender when prescribing opioid medications.

Urban scaling of opioid analgesic sales in the United States.

Opioid misuse is a public health crisis in the United States. The origin of this crisis is associated with a sharp increase in opioid analgesic prescribing. We used the urban scaling framework to analyze opioid prescribing patterns in US commuting zones (CZs), i.e., groups of counties based on commuting patterns. The urban scaling framework postulates that a set of scaling relations can be used to predict health outcomes and behaviors in cities. We used data from the Drug Enforcement Administration's Automated Reports and Consolidated Ordering System (ARCOS) to calculate counts of oxycodone/hydrocodone pills distributed to 607 CZs in the continental US from 2006 to 2014. We estimated the scaling coefficient of opioid pill counts by regressing log(pills) on log(population) using a piecewise linear spline with a single knot at 82,363. Our results show that CZs with populations below the knot scaled superlinearly (ß = 1.36), i.e., larger CZs had disproportionally larger pill counts compared to smaller CZs. On the other hand, CZs with populations above the knot scaled sublinearly (ß = 0.92), i.e., larger CZs had disproportionally smaller pill counts compared to smaller CZs. This dual scaling pattern was consistent across US census regions. For CZs with population below the knot, the superlinear scaling of pills is consistent with the explanation that an increased number of successful matches between prescribers and users will lead to higher prescribing rates. The non-linear scaling behavior observed could be the result of a combination of factors, including stronger health care systems and prescribing regulation in largely populated commuting zones, as well as high availability of other opioids such as heroin in these commuting zones. Future research should explore potential mechanisms for the non-linearity of prescription opioid pills.

An observational cohort study comparing ibuprofen and oxycodone in children with fractures.

OBJECTIVE: To compare the effectiveness and safety of prescribing ibuprofen and oxycodone for at-home management of children's fracture pain. METHODS: A prospective observational cohort was conducted at the Stollery Children's Hospital pediatric emergency department (June 2010-July 2014). Children aged 4-16 years with an isolated fracture discharged home with advice to use either ibuprofen or oxycodone were recruited. RESULTS: A cohort of 329 children (n = 217 ibuprofen, n = 112 oxycodone) were included. Mean age was 11.1 years (SD 3.5); 68% (223/329) were male. Fracture distribution included 80.5% (264/329) upper limb with 34.3% (113/329) requiring fracture reduction. The mean reduction in Faces Pain Score-Revised score (maximum pain-post-treatment pain) for Day 1 was 3.6 (SD 1.9) (ibuprofen) and 3.8 (SD 2.1) (oxycodone) (p = 0.50); Day 2 was 3.6 (SD 1.8) (ibuprofen) and 3.7 (SD 1.6) (oxycodone) (p = 0.56); Day 3 was 3.7 (SD 1.7) (ibuprofen) and 3.3 (SD 1.7) (oxycodone) (p = 0.24). Children prescribed ibuprofen (51.2%, 109/213) experienced less adverse events compared to those prescribed oxycodone (70.5% 79/112) on Day 1 (p = 0.001). Children prescribed ibuprofen (71.8%, 150/209) had their function (eat, play, school, sleep) affected less than those prescribed oxycodone (83.0%, 93/112) (p = 0.03) on Day 1. CONCLUSION: Children prescribed ibuprofen or oxycodone experienced similar analgesic effectiveness for at-home fracture pain. Oxycodone prescribing was associated with more adverse events and negatively impacted function. Oxycodone use does not appear to confer any benefit over ibuprofen for pain relief and has a negative adverse effect profile. Ibuprofen appears to be a safe option for fracture-related pain.

Sex and Estrous Cycle Differences in Analgesia and Brain Oxycodone Levels.

Sex differences in opioid analgesia occur in rodents and humans, and could be due to differences in drug and metabolite levels. Thus, we investigated the sex and cycle differences in analgesia (nociception) from oxycodone in rats and related these to sex and cycle differences in brain and plasma oxycodone and metabolite levels. Since numerous opioids are CYP2D enzyme substrates and variation in CYP2D alters opioid drug levels and response, we also initiated studies to see if the sex and cycle differences observed might be due to differences in brain CYP2D activity. Across oxycodone doses, females in diestrus had higher analgesia (using tail flick latency) compared to males and females in estrus; we also demonstrated a direct effect of estrous cycle on analgesia within females. Consistent with the analgesia, females in diestrus had highest brain oxycodone levels (assessed using microdialysis) compared to males and females in estrus. Analgesia correlated with brain oxycodone, but not brain oxymorphone or noroxycodone levels, or plasma drug or metabolite levels. Propranolol (a CYP2D mechanism-based inhibitor), versus vehicle pre-treatments, increased brain oxycodone, and decreased brain oxymorphone/oxycodone drug level ratios (an in vivo CYP2D activity phenotype in the brain) in males and females in estrus, but not in females in diestrus. Brain oxymorphone/oxycodone inversely correlated with analgesia. Together, both sex and estrous cycle impact oxycodone analgesia and brain oxycodone levels, likely through regulation of brain CYP2D oxycodone metabolism. As CYP2D6 is expressed in human brain, perhaps similar sex and cycle influences also occur in humans.

Tapentadol in Cancer Patients with Neuropathic Pain: A Comparison of Methadone, Oxycodone, Fentanyl, and Hydromorphone.

Tapentadol has µ-opioid receptor stimulating and noradrenaline reuptake inhibiting properties, and should be effective for neuropathic pain (NP). However, the efficacy of tapentadol for NP in cancer patients is unclear. Ashiya Municipal Hospital (Hyogo, Japan) enrolled five groups of Japanese cancer patients between January 1, 2013, and December 31, 2019. Patients with NP were administered tapentadol (n = 29), methadone (n = 32), oxycodone (n = 20), fentanyl (n = 26), or hydromorphone (n = 20). The primary endpoint was the difference in the verbal rating scale (VRS) scores between days 0 and 7. The secondary endpoint was the tolerability of each opioid. Before administering opioids among the five groups, there was no significant difference in the VRS score (p = 0.99). The mean reduction in the VRS score on day 7 was significantly greater in the tapentadol group than in the oxycodone group (p = 0.0024) and was larger than that of the methadone, fentanyl, and hydromorphone groups. Regarding safety, the discontinuation rate in the tapentadol group was the lowest of all groups (tapentadol vs. methadone vs. oxycodone vs. fentanyl vs. hydromorphone, 0.0% vs. 6.3% vs. 5.0% vs. 3.8% vs. 10.0%, respectively). This study suggests that tapentadol could be efficacious for cancer patients with NP, and a preferred option in cases that require immediate dose adjustment or for those at high risk for adverse effects. However, the pain intensity was evaluated without pain assessment scales specific to NP. Thus, we think that it is desirable to validate our findings using assessment scales, such as the painDETECT questionnaire in future.

Sex and heredity are determinants of drug intake in a novel model of rat oral oxycodone self-administration.

The steady rise in prescription opioids such as oxycodone has led to a virulent epidemic of widespread abuse and deaths in the United States; approximately 80% of affected individuals initiate the habitual use of oxycodone by using prescription oral oxycodone. Given the importance of drug pharmacokinetics in determining abuse potential, we designed an oral operant oxycodone self-administration (SA) procedure in rats to model drug intake by most human users/abusers of oxycodone. Key aspects of the model include limited initial drug intake followed by increasing drug concentrations during extended 4-h sessions on alternating days. Sex and genetic predisposition are major determinants of human opiate abuse. Therefore, we studied females in seven inbred strains (WLI, WMI, LEW, DSS, F344, BN and SHR) and both sexes in three of these strains. All strains increased intake across serially increasing doses (0.025-0.2 mg/ml; p < 0.001): the range of intakes at the final concentration of oxycodone was 0.72 ± 0.17-4.84 ± 1.42 mg/kg (mean ± SEM) - a 6.7-fold difference across strains. In LEW, WLI and WMI strains, oxycodone intake increased significantly across all sessions in both sexes. However, in LEW and WMI male rats but not WLI, daily oxycodone intake was significantly lower across all 4-h sessions than females (p < 0.005). The estimated heritability in oxycodone intake was in the range of 0.21-0.41. In summary, our novel operant oral oxycodone SA model captures the strong abuse potential of oral oxycodone and shows dose, sex and strain-specific drug intake that is significantly dependent on heredity.

The effects of tapentadol and oxycodone on central processing of tonic pain.

OBJECTIVE: The present study investigated differences between opioids to experimental tonic pain in healthy men. METHODS: Twenty-one males participated in this cross-over-trial. Interventions twice daily were oxycodone (10 mg), tapentadol (50 mg) and placebo for 14 days. Tonic pain was induced on day 1, 4 and 14 by immersing the hand in 2 °C water for 120 s. Electroencephalography was recorded during test pain at baseline and after 14 days. Spectral analysis and source localization were investigated in predefined frequency bands. RESULTS: A decreased perception of pain on day 4 persisted throughout the 14 days compared to baseline (p < 0.006). Oxycodone decreased the electroencephalography spectral power in the delta and theta bands and increased power in the alpha1, alpha2 and beta1 bands (p < 0.03). Tapentadol increased spectral power in the alpha1 band (p < 0.001). Source localization revealed that oxycodone decreased activity of the temporal and limbic region in the delta band, and frontal lobe in the alpha2 and beta1 bands, whereas tapentadol decreased alpha1 band activity in the temporal lobe compared to placebo. CONCLUSION: Oxycodone and tapentadol reduced pain perception and changed the central processing of tonic pain. SIGNIFICANCE: Different mechanisms of action were involved, where oxycodone affected cortical structures more than tapentadol.

Assessment of Opioid Use and Analgesic Requirements After Endoscopic Sinus Surgery: A Randomized Clinical Trial.

Importance: The opioid epidemic has generated interest in optimizing opioid prescribing after common surgeries. Recent studies have shown a broad range of analgesic prescription patterns following endoscopic sinus surgery (ESS). Objective: To compare the efficacy of different analgesic regimens after ESS. Design, Setting, and Participants: This multi-institutional, nonblinded randomized clinical trial was conducted at 6 tertiary centers across the US and Canada and included participants who underwent ESS for acute or chronic rhinosinusitis. The study was conducted from March 2019 to March 2020, and the data were analyzed in November to December 2020. Interventions: All participants received acetaminophen, 650 mg, as the first-line analgesic. From there, patients were randomized to either oxycodone rescue (oxycodone, 5 mg, as second-line therapy) or ibuprofen rescue (ibuprofen, 600 mg, as second-line therapy, with oxycodone, 5 mg, reserved for breakthrough pain). Main Outcomes and Measures: Baseline characteristics and disease severity were collected at enrollment. Medication logs, pain scores, and epistaxis measures were collected until postoperative day 7. The primary outcome was the postoperative visual analog scale score for pain. Brief Pain Inventory Pain Severity and Pain Interference Scores were also collected. Results: A total of 118 patients were randomized (62 [52.5%] oxycodone rescue, 56 [47.5%] ibuprofen rescue; mean [SD] age, 46.7 [16.3] years; 44 women [44.0%]; 83 White [83.0%], 7 Black [7.0%], and 7 Asian individuals [7.0%]). After exclusions for loss to follow-up and noncompliance, 51 remained in the oxycodone rescue group and 49 in the ibuprofen rescue group. The groups had similar demographic characteristics and disease severity. Thirty-two (63%) in the oxycodone rescue group had adequate pain management with acetaminophen only, while 19 (37%) consumed at least 1 oxycodone dose. In the ibuprofen rescue group, 18 (16%) required only acetaminophen, 28 (57%) used only acetaminophen and ibuprofen, and the remaining 13 (26%) consumed 1 or more oxycodone doses. The groups had similar average acetaminophen (9.69 vs 7.96 doses; difference, 1.73; 95% CI, -1.37 to 4.83) and oxycodone (1.89 vs 0.77 doses; difference, 1.13; 95% CI, -0.11 to 2.36) use. Both groups had similar postoperative visual analog scale scores. A subanalysis that compared opioids users with nonusers showed clinically significant lower pain scores in nonusers at multiple postoperative points. Conclusions and Relevance: In this randomized clinical trial, most patients who underwent ESS could be treated postoperatively using a nonopioid regimen of either acetaminophen alone or acetaminophen and ibuprofen. Ibuprofen as a second-line therapy did not reduce overall narcotic consumption, but the overall narcotic use was low in both groups. Trial Registration: ClinicalTrials.gov Identifier: NCT03783702.

Lower Background Infusion of Oxycodone for Patient-Controlled Intravenous Analgesia, Combined with Ropivacaine Intercostal Nerve Block, in Patients Undergoing Thoracoscopic Lobectomy for Lung Cancer: A Randomized, Double-Blind, Controlled Clinical Trial.

PURPOSE: To compare the efficacy of a lower dose background infusion of oxycodone for patient-controlled intravenous analgesia (PCIA) with the conventional dose, following intercostal nerve block, for the management of postoperative pain in patients undergoing thoracoscopic lobectomy for lung cancer. PATIENTS AND METHODS: This was a prospective, single-center, randomized, parallel-group, double-blind, controlled clinical trial. In total, 155 patients scheduled for elective radical lobectomy via video-assisted thoracoscopy were recruited from December 2018 to July 2019, of whom 140 were ultimately included in the study population. Patients were randomized to receive either oxycodone 0.25 mg/h (low-dose group, n=70) or oxycodone 0.5 mg/h (control group, n=70) as a background infusion for PCIA, following ropivacaine intercostal nerve block, for postoperative pain management. The primary endpoints were rest and dynamic visual analogue scale (VAS) scores within 72 h of the operation. The secondary endpoints were patient satisfaction scores, consumption of postoperative analgesics, times of patient-controlled analgesia (PCA), and adverse events. RESULTS: All 140 enrolled patients completed the study requirements and were included in the final analysis. The rest and dynamic VAS scores at 4 h, 24 h, 48 h, and 72 h postoperative were comparable between the low-dose group and the control group (P>0.05). However, the low-dose group had statistically significantly higher patient satisfaction scores (P<0.001) and lower postoperative analgesic consumption (P<0.001) as well as lower incidence of nausea and vomiting (P<0.05). The times of PCA was not statistically significantly different between the two groups, and no serious adverse events occurred in either group (P>0.05). CONCLUSION: A low-dose background infusion of oxycodone for postoperative PCIA can achieve a comparable analgesic effect to the conventional dose after thoracoscopic lobectomy for lung cancer. Furthermore, the low-dose regimen was associated with reduced consumption of oxycodone and increased patient satisfaction.

Oxycodone versus morphine for analgesia after laparoscopic endometriosis resection.

BACKGROUND: The objective of this study was to compare the analgesic potency of oxycodone versus morphine after laparoscopic deep infiltrating endometriosis resection. METHODS: Fifty patients undergoing laparoscopic deep infiltrating endometriosis resection were randomized to receive oxycodone or morphine intravenous-PCA after surgery. The primary outcome was opioid consumption during the 24 h after surgery. Secondary outcomes included time to first request for analgesia, the number of bolus, pain, sedation, nausea, vomiting, respiratory depression, and bradycardia. The prominent pain that caused patients to press the analgesic device was also recorded. RESULTS: Oxycodone consumption (14.42 ± 2.83) was less than morphine consumption (20.14 ± 3.83). Compared with the morphine group, the total number of bolus (78 vs 123) was less and the average time to first request for analgesia (97.27 ± 59.79 vs 142.17 ± 51) was longer in the oxycodone group. The incidence of nausea was higher in the morphine group than in the oxycodone group at 0-2 h (45.45% vs 17.19%), 2-4 h (50% vs 17.19%),12-24 h (40.91% vs 13.04%) and 0-24 h (39.17% vs 19.13%). The overall incidence of vomiting was higher in the morphine group (27.27% vs 13.92%). There was no difference in visual analogue scale score, the incidence of respiratory depression, and bradycardia between groups. Of the three types of pain that prompted patients to request analgesia, the incidence of visceral pain was highest (59.9%, P < 0.01). CONCLUSION: Oxycodone was more potent than morphine for analgesia after laparoscopic endometriosis resection, and oxycodone has fewer side effects than morphine. Name of the registry: Chinese Clinical Trial Registry Trial registration number: ChiCTR1900021870 URL of trial registry record: http://www.chictr.org.cn/edit.aspx?pid=35799&htm=4 Date of registration: 2019/3/13 0:00:00.

Educational Video on Pain Management and Subsequent Opioid Use After Cesarean Delivery: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether viewing an educational video on pain management reduces opioid use after cesarean delivery. METHODS: We conducted a randomized, controlled trial of women aged 18 years or older who underwent cesarean delivery at a tertiary care center. Eligible women were randomized in a 1:1 ratio to usual discharge pain medication instructions plus an educational video on pain management or to usual discharge pain medication instructions alone. All women received the same opioid prescription at discharge: Twenty 5-mg oxycodone tablets. Participants were contacted at 7 days and at 14 days after delivery to assess the number of oxycodone tablets used, adjunct medication (acetaminophen and ibuprofen) use, pain scores, and overall satisfaction of pain control. The primary outcome was the number of oxycodone tablets used from discharge through postpartum day 14. A sample size of 23 per group (n=46) was planned to detect a 25% difference in mean number of oxycodone tablets used between groups, as from 20 to 15. RESULTS: From July 2019 through December 2019, 61 women were screened and 48 were enrolled-24 in each group. Women who viewed the educational video used significantly fewer opioid tablets from discharge through postpartum day 14 compared with women who received usual pain medication instructions (median 1.5, range 0-20 vs median 10, range 0-24, P<.001). Adjunct medication use, pain scores, and satisfaction with pain control did not differ significantly between groups. CONCLUSION: Among women who underwent cesarean delivery, viewing an educational video on pain management reduced postdischarge opioid use. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03959969.

Minocycline attenuates oxycodone-induced positive subjective responses in non-dependent, recreational opioid users.

BACKGROUND: Recent data suggest that glial cells may be involved in the analgesic effects and abuse liability of opioids. Preclinical studies have demonstrated that mu-opioid-receptor-selective agonists, such as oxycodone, activate glia and increase the release of cytokines, causing a suppression of opioid-induced analgesic effects. Preclinical studies also show that certain medications, such as the broad-spectrum tetracycline antibiotic minocycline, inhibit opioid-induced glial activation and thereby enhance the analgesic effects of opioids. Importantly, minocycline reduces the rewarding effects of opioids at the same doses that it enhances opioid-induced analgesia. AIMS: The purpose of the present study was to assess the effects of acute administration of minocycline on the subjective, physiological, and analgesic effects of oxycodone in human research volunteers. DESIGN: This study was a within-subject, randomized, double-blind outpatient study. Participants completed five separate sessions in which they received 0, 100, or 200 mg minocycline (MINO) simultaneously with either 0 or 40 mg oxycodone (OXY). The subjective, physiological, and analgesic effects of OXY were measured before and repeatedly after drug administration. SETTINGS AND PARTICIPANTS: Participants were between 21 and 45 years of age, non-treatment seeking, non-dependent recreational opioid users (N = 12). This study was conducted between 2013 and 2014 at the New York State Psychiatric Institute in New York, NY. FINDINGS: MINO 100 and 200 mg were safe and well-tolerated in combination with OXY 40 mg. MINO 200 mg administered with OXY 40 mg attenuated OXY-induced positive subjective effects such as "Good Effect" and "Liking" compared to OXY alone. MINO did not alter the physiological or analgesic effects of OXY. CONCLUSIONS: MINO may attenuate the abuse liability of mu-opioid-receptor-selective agonists.