Administration Of Hydromorphone Research Articles

Successful pain control with add-on methadone for refractory neuropathic pain due to radiation necrosis in pontine metastatic lesion: a case report

BackgroundCentral pain, characterized by neuropathic pain, can manifest due to injury to the superior spinothalamic tract. The brainstem includes sensory and motor pathways as well as nuclei of the cranial nerves, and therefore cancer metastasis in the region requires early intervention. Although stereotactic radiosurgery (SRS) is commonly employed for the treatment of brain metastasis, it poses risks of late complications like radiation necrosis (RN). RN exacerbates the progression of brain lesions within the irradiated area, and in the brainstem, it can damage multiple nerves, including the superior spinothalamic tract. Central neuropathic pain is often intractable and empirically managed with a combination of conventional drugs, such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and anticonvulsants. However, their efficacy is often limited, leading to a decline in performance status (PS) and quality of life (QOL).Case presentationWe present the case of a 53-year-old man diagnosed with stage IV lung cancer, referred to our palliative care team for managing severe central pain resulting from SRS-related RN in the pons. Despite administration of opioids, including oxycodone and hydromorphone, and adjuvant analgesics, the patient continued to require frequent use of immediate-release opioids. The addition of methadone alone proved successful in achieving optimal pain control.ConclusionsProvided that RN in the brainstem can lead to intractable neuropathic pain, it is advisable to avoid SRS for brainstem metastasis when possible. Add-on methadone should be considered as a viable pain management medication for patients experiencing unresolved central pain.

Fentanyl Analogs Exert Antinociceptive Effects via Sodium Channel Blockade in Mice.

The formalin test is one approach to studying acute pain in rodents. Similar to formalin, injection with glutamate and veratrine can also produce a nociceptive response. This study investigated whether opioid-related compounds could suppress glutamate- and veratrine-induced nociceptive responses in mice at the same dose. The administration of morphine (3 mg/kg), hydromorphone (0.4 mg/kg), or fentanyl (0.03 mg/kg) suppressed glutamate-induced nociceptive response, but not veratrine-induced nociceptive response at the same doses. However, high doses of morphine (10 mg/kg), hydromorphone (2 mg/kg), or fentanyl (0.1 mg/kg) produced a significant reduction in the veratrine-induced nociceptive response. These results indicate that high doses are required when using morphine, hydromorphone, or fentanyl for sodium channel-related neuropathic pain, such as ectopic activity. As a result, concerns have arisen about overdose and abuse if the dose of opioids is steadily increased to relieve pain. In contrast, trimebutine (100 mg/kg) and fentanyl analog isobutyrylfentanyl (iBF; 0.1 mg/kg) suppressed both glutamate- and veratrine-induced nociceptive response. Furthermore, nor-isobutyrylfentanyl (nor-iBF; 1 mg/kg), which is a metabolite of iBF, suppressed veratrine-induced nociceptive response. Besides, the optimal antinociceptive dose of iBF, unlike fentanyl, only slightly increased locomotor activity and did not slow gastrointestinal transit. Cancer pain is a complex condition driven by inflammatory, neuropathic, and cancer-specific mechanisms. Thus, iBF may have the potential to be a superior analgesic than fentanyl.

Pharmacokinetics of a continuous intravenous infusion of hydromorphone in healthy dogs.

Dosing recommendations for hydromorphone intravenous constant rate infusion (IV CRI) are derived from simulations following IV bolus administration. While this extrapolated dose regimen has been described clinically, pharmacokinetics (PK) of hydromorphone infusions in dogs are not yet described. The study objective was to describe the PK of hydromorphone in healthy dogs receiving an IV bolus followed by an IV CRI for 48 h. A prospective, experimental study was performed involving the administration of hydromorphone (0.1 mg/kg IV bolus then IV CRI 0.01 mg/kg/h over a 48 h period) to 6 healthy Beagle dogs. Blood samples were collected at 16 time points between 0 and 58 h relative to the initial bolus. Plasma hydromorphone concentrations were analyzed by high pressure liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameter estimates were obtained with compartmental methods using commercially available software. A two-compartment model with first order elimination was used. At the end of the infusion, median (range) plasma hydromorphone concentrations were 6.8 (5.5-19.6) ng/mL. The median total body clearance was 30.4 (19.8-36.7) mL/min/kg; volume of distribution at steady state was 4.5 (3.2-7.8) L/kg; and terminal elimination half-life was 11.2 (7.6-24.3) h. Hydromorphone (0.1 mg/kg IV bolus then IV CRI of 0.01 mg/kg/h) maintained steady-state plasma concentrations above the minimum human analgesic target in healthy Beagle dogs with minimal side effects. Further studies are needed to determine the effective plasma concentrations of hydromorphone in painful dogs.

Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-‍linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Pharmacokinetics of hydrorphone hydrochloride after intravenous and subcutaneous administration in ferrets (Mustela putorius furo)

ObjectiveTo determine the pharmacokinetic profile of hydromorphone 0.2 mg kg–1 administered by the intravenous (IV) and subcutaneous (SC) route in ferrets. Study designRandomized, crossover study. AnimalsA group of eight adult ferrets weighting (mean ± standard deviation) 1.02 ± 0.22 kg. MethodsHydromorphone hydrochloride 0.2 mg kg–1 was administered IV or SC with a washout period of 7 days. Blood samples were collected from a jugular catheter before administration of hydromorphone and at 5, 10, 15, 20, 30, 45, 60, 90, 120, 240, 360, 480 and 720 minutes after hydromorphone administration. Plasma hydromorphone concentrations were determined by liquid chromatography/tandem mass spectrometry. Data were analyzed using a non-linear mixed effects model. ResultsThe hydromorphone effective half-life was (t1/2) 45 min–1. Systemic clearance (Cls) and the volume of distribution (Vdss) following IV administration were 84.8 mL kg–1 min–1 and 5.59 L kg–1, respectively. The maximum observed plasma concentration was 59.53 ± 14.02 ng mL–1 within 10 minutes following SC administration. The SC bioavailability was 102.0%. Conclusions and clinical relevanceAdministration of IV and SC hydromorphone (0.2 mg kg–1) was characterized by a high clearance, short terminal half-life and large volume of distribution. Hydromorphone plasma concentrations remained greater than 2 ng mL–1 for 2 hours in most ferrets, a threshold reported to provide antinociceptive effects in other species. Hydromorphone was well absorbed following SC injection, providing an alternative administration route for clinical use in ferrets.

Subcutaneous administration of hydromorphone (0.2 mg/kg) provides antinociception in ferrets (Mustela putorius furo).

To evaluate antinociceptive efficacy of SC administration of hydromorphone hydrochloride and buprenorphine hydrochloride in ferrets (Mustela putorius furo). 14 healthy adult ferrets (6 neutered males, 8 spayed females). In a randomized, blind, controlled, complete crossover design, all 14 ferrets received a single, SC injection of hydromorphone low dose (0.1 mg/kg), hydromorphone high dose (0.2 mg/kg), buprenorphine low dose (0.02 mg/kg), buprenorphine high dose (0.04 mg/kg), or saline solution (0.2 mL/kg). Sedation and forelimb withdrawal latency from a noxious thermal stimulation were evaluated, and behavior was recorded for a total of 8 hours postinjection. Compared to saline, administration of hydromorphone at 0.2 mg/kg resulted in an estimated increase of withdrawal latencies of 7.4 seconds (95% CI, 3.2 to 11.6) at 60 minutes, of 6.6 seconds (2.4 to 10.8) at 90 minutes, of 6.0 seconds (1.8 to 10.2) at 120 minutes, of 7.0 seconds (2.9 to 11.1) at 180 minutes, and of 4.5 seconds (0.5 to 8.6) at 240 minutes. These differences were statistically significant. Hydromorphone administered at a lower dose and buprenorphine at either dose did not increase withdrawal latencies compared to saline. Based on the sedation score used in this study, signs of sedation increased over time in a similar fashion with all treatments, including saline. Erratic dysphoric-like behaviors occurred in all groups except for saline. SC administration of hydromorphone at a dose of 0.2 mg/kg provided antinociception from 1 to 4 hours postinjection. Further validation of sedation scores in ferrets is warranted.

47 Investigating links between pigmentation genes and opioid effectiveness in horses

The pleiotropic effects of the melanocortin system show promise in overcoming limitations associated with large variations in opioid analgesic effectiveness observed in equine practice. Of particular interest is the melanocortin-1-receptor gene (MC1R), which influences melanin type through its epistatic interaction with the agouti signaling protein gene (ASIP), dictating the production of black or red pigment. MC1R has previously been associated with opioid effectiveness in other species; however, evidence of similar relationships in horses is lacking. As such, this study investigated if associations between opioid response and pigmentation genes were also observable in horses. Nociceptive response data were opportunistically collected during the performance of spinal fluid centesis (SFC), noting the pain response of individual horses after sedation. A target dosage range of 0.01–0.02 mg/kg body weight intravenously was used in the administration of the opioid hydromorphone, the primary drug of interest in this study. Genomic regions responsible for the bay (ASIP) and chestnut (MC1R) coat colors were extracted from genome sequence data, and opioid analgesic effectiveness was scored (1–3) based on pain response for each horse (n = 48). Haplotype and SNP association analyseswere performed using the SNPassoc (testing multiple models) and haplo.stats packages and generalized linear models within the statistical software R. Age, breed, sex, and dosage rates were recorded as covariates. Breeds with less than 2 horses were excluded from analyses. Six single-nucleotide polymorphisms (SNPs) within ASIP and one within MC1R were identified as significantly (P < 0.05) associated with opioid analgesic effectiveness during SFC. Haplotype analysis of the significant ASIP SNPs revealed that the most common ASIP haplotype was associated with lower opioid analgesic effectiveness, both in isolation and when looked at in conjunction with MC1R. The recessive MC1Re/e mutation resulting in the production of red pigment only was also significantly associated with decreased opioid analgesic effectiveness. The current study provides promising evidence for important links between pigmentation genes and opioid effectiveness in horses. However, given the complexity of opioid metabolism and the opportunistic nature of the current study, additional investigations are needed if precision medicine approaches are to become a reality in equine veterinary medicine.

Intraoperative hydromorphone decreases postoperative pain: an instrumental variable analysis

BackgroundIntraoperative administration of short-acting opioids might lead to increased postoperative pain and opioid requirements. There are few data describing the effects of intermediate-duration opioids such as hydromorphone on these outcomes. We have previously shown that a switch from a 2 mg to a 1 mg vial of hydromorphone was associated with decreased intraoperative dose administration. As presentation dose affected intraoperative hydromorphone administration and was unrelated to other policy changes, it could serve as an instrumental variable, assuming significant secular trends were not present during the study period. MethodsIn this observational cohort study of patients who received intraoperative hydromorphone (n=6750), an instrumental variable analysis was used to evaluate whether intraoperative hydromorphone administration affected postoperative pain scores and opioid administration. Before July 2017, hydromorphone was available as a 2-mg unit dose. From July 1, 2017 to November 20, 2017, hydromorphone was only available in a 1-mg unit dose. A two-stage least squares regression analysis was used to estimate causal effects. ResultsA 0.2-mg increase in intraoperative hydromorphone administration caused a decrease in admission PACU pain scores (mean difference, –0.8; 95% confidence interval, –1.2 to –0.4; P<0.001) and decreased maximum and time-weighted mean pain scores over 2 days postoperatively, without increased opioid administration. ConclusionsThis study suggests that intraoperative administration of intermediate-duration opioids does not cause the same effects as short-acting opioids with respect to postoperative pain. Instrumental variables can be used to estimate causal effects using observation data when unmeasured confounding is present.

Hydromorphone Prescription for Pain in Children-What Place in Clinical Practice?

While morphine is the gold standard treatment for severe nociceptive pain in children, hydromorphone is increasingly prescribed in this population. This review aims to assess available knowledge about hydromorphone and explore the evidence for its safe and effective prescription in children. Hydromorphone is an opioid analgesic similar to morphine structurally and in its pharmacokinetic and pharmacodynamic properties but 5–7 times more potent. Pediatric pharmacokinetic and pharmacodynamic data on hydromorphone are sorely lacking; they are non-existent in children younger than 6 months of age and for oral administration. The current data do not support any advantage of hydromorphone over morphine, both in terms of efficacy and safety in children. Morphine should remain the treatment of choice for moderate and severe nociceptive pain in children and hydromorphone should be reserved as alternative treatment. Because of the important difference in potency, all strategies should be taken to avoid inadvertent administration of hydromorphone when morphine is intended.

Pattern of hydromorphone use in King Abdulaziz Medical City-Central Region (KAMC-CR)

Hydromorphone is a semi-synthetic opioid that acts mainly on the μ-opioid receptor. Hydromorphone has a fast onset of action, usually within 5 min, and its effectiveness peaks at approximately 20 min, which makes it favourable in the postoperative setting. It plays a role in the management of moderate to severe chronic pain. The most common adverse effects of hydromorphone are hypotension, bradycardia, and respiratory distress. The aim of this study was to determine the trend in the use of hydromorphone analgesics and to evaluate hydromorphone-related toxicity in King Abdulaziz Medical City-Central Region (KAMC-CR). A retrospective, cross-sectional study was carried out in KAMC-CR, and medical and pharmacological data were retrieved from electronic health records for adult patients who used hydromorphone between December 2014 and December 2015. The characteristics of the enrolled patients, including measured blood pressure, heart rate, respiration rate, oxygen saturation, and pain severity score, were collected. Moreover, we identified patients who received naloxone as a hydromorphone antidote. A total of 153 patients were included; 64.1% were male and 35.8% were female. The mean age of the included patients was 55.5 years old (+/− 18.6). Although the majority of patients reported an improvement in pain severity, 75 patients (49%) needed naloxone to overcome adverse effects of hydromorphone. The mean age of patients who received naloxone was 56.2 years old (+/− 20.5), their mean weight was 75.9 kg (+/− 17.2), and 61.3% of them were male (n = 46). Among those who received naloxone, 84% patients (n = 63) had received hydromorphone intravenously. The risk of respiratory depression was significantly higher in patients who received hydromorphone intravenously (IV) than in those who received it orally (p = 0.02). Hydromorphone can have adverse effect. Thus, we recommend evaluating cardiac parameters, oxygen saturation, respiration rate, and pain severity before administering hydromorphone, particularly in patients who have a high risk of cardiorespiratory adverse events, such as patients with cardiac disease, asthma, or chronic obstructive pulmonary disease. Additionally, we recommend the use of appropriate hydromorphone doses in cases of conversion from other opioid therapy or changes between oral and IV routes of the administration of hydromorphone. Moreover, we recommend establishing a policy to restrict the prescription of hydromorphone to avoid the overuse of hydromorphone and minimize the risk of adverse effects and medication errors.

Effect of Methadone or Hydromorphone on Cardiac Conductivity in Dogs Before and During Sevoflurane Anesthesia.

Objective: To evaluate changes in electrocardiogram (ECG) variables in healthy dogs receiving either methadone or hydromorphone IV before and during sevoflurane anesthesia.Study Design: Prospective clinical study.Animals: Forty client-owned dogs.Methods: Dogs were randomized to receive methadone 0.5 mg/kg IV or hydromorphone 0.1 mg/kg IV in each part of a two-part study. In part one, dogs received the opioid prior to sevoflurane anesthesia (groups MS, n = 12 and HS, n = 12). Anesthesia was induced with propofol IV, maintained with sevoflurane, and dogs were mechanically ventilated. Standard 6-lead ECG recordings were obtained before opioid administration, 2, 5, and 10 min after opioid administration prior to anesthesia, and during anesthesia 15 min after end-tidal sevoflurane stabilized at 2.4%. In part two, conscious dogs received the same opioid treatments and ECGs were obtained at equivalent time points without undergoing anesthesia (groups M, n = 8 and H, n = 8). Values for ECG variables were determined by a blinded cardiologist and included: Heart rate (HR), PR interval, QT interval, and HR corrected QT interval (QTc) using the Bazett (QTcB), Fridericia (QTcF), and Van de Water (QTcV) formulas. Differences over time and between all four groups were evaluated using ANOVA for repeated measures with significance set at p ≤ 0.05.Results: Both methadone and hydromorphone administration reduced HR and prolonged PR and QT intervals, with greater changes observed during sevoflurane anesthesia. The greatest prolongation in QT interval was observed in dogs administered methadone during sevoflurane anesthesia.Conclusions and Clinical Relevance: Methadone and hydromorphone caused disturbances in myocardial electrical activity, and the addition of sevoflurane enhanced these disturbances. Both drugs caused considerable QT interval prolongation into the proarrhythmogenic range, with methadone causing greater prolongation.

A retrospective evaluation of the effect of perianesthetic hydromorphone administration on the incidence of postanesthetic signs of colic in horses

ObjectiveTo describe the incidence of postanesthetic signs of colic (PASC) in horses and determine if perianesthetic administration of hydromorphone was associated with an increased risk of PASC. Study designRetrospective, cohort study. AnimalsA total of 409 horses. MethodsAnesthesia and clinical records of horses admitted for various procedures from July 2018 to September 2019 were reviewed. Signs of colic and interventions were recorded up to 48 hours after anesthesia. A binomial logistic regression model was used to evaluate the association between the type of surgery, administration of hydromorphone, the duration of anesthesia and the incidence of PASC. ResultsOverall, 25 (6.1%) horses developed PASC within 48 hours of general anesthesia. Of 60 horses that underwent colic surgery, 16 (26.7%) developed PASC. Of 349 horses that underwent noncolic procedures, nine (2.6%) developed PASC. Thus, the incidence of PASC was higher in horses that underwent colic surgery than in horses that underwent noncolic procedures [odds ratio (OR) = 13.74 (5.73–32.95)]. No effect of hydromorphone on the incidence of PASC was identified [OR = 1.61 (0.71–3.62)]. Longer procedures (>2 hours) were identified as an independent risk factor for PASC [OR = 4.13 (1.52–11.22)]. ConclusionsNo association between hydromorphone and an increase in the incidence of PASC was identified. Anesthesia for colic surgery and duration of anesthesia were associated with an increased risk of PASC. Clinical relevanceHydromorphone did not increase the incidence of PASC in this population.

Single dose epidural hydromorphone in labour pain: maternal pharmacokinetics and neonatal exposure

IntroductionEpidural hydromorphone could be useful in obstetric analgesia as there is a need for a more water-soluble opioid than sufentanil or fentanyl with prolonged analgesic effect. To our knowledge, the pharmacokinetics of epidural hydromorphone has not been evaluated in parturients.Materials and methodsIn this pilot study, seven healthy parturients were given a single epidural dose of hydromorphone for labour pain. One parturient received 1.5 mg, two 0.75 mg and four 0.5 mg of hydromorphone hydrochloride. Dose was decreased due to nausea and pruritus. Hydromorphone’s effect, adverse effects and plasma concentrations were evaluated. Neonatal drug exposure was evaluated by umbilical vein and artery opioid concentration at birth. Neonatal outcomes were assessed using Apgar and the Neurologic Adaptive Capacity Score (NACS).ResultsAll patients received additional levobupivacaine doses on parturients’ requests. The first dose was requested at a median of 163 min (range 19–303 min) after hydromorphone administration. A total of 12 opioid related expected adverse events were reported by seven parturients. All newborn outcomes were uneventful. Hydromorphone’s distribution and elimination after single epidural dose seem similar to that reported for non-pregnant subjects after intravenous hydromorphone administration, but further research is required to confirm this observation.ConclusionsThe optimal dose of hydromorphone in labour pain warrants further evaluation.

High-Frequency Heart Rate Variability Index: A Prospective, Observational Trial Assessing Utility as a Marker for the Balance Between Analgesia and Nociception Under General Anesthesia.

Maintaining a balance between nociception and analgesia perioperatively reduces morbidity and improves outcomes. Current intraoperative analgesic strategies are based on subjective and nonspecific parameters. The high-frequency heart rate (HR) variability index is purported to assess the balance between nociception and analgesia in patients under general anesthesia. This prospective observational study investigated whether intraoperative changes in the high-frequency HR variability index correlate with clinically relevant nociceptive stimulation and the addition of analgesics. Instantaneous and mean high-frequency HR variability indexes were measured continuously in 79 adult subjects undergoing general anesthesia for laparoscopic cholecystectomy. The indexes were compared just before and 2 minutes after direct laryngoscopy, orogastric tube placement, first skin incision, and abdominal insufflation and just before and 6 minutes after the administration of IV hydromorphone. Data from 65 subjects were included in the final analysis. The instantaneous index decreased after skin incision ([SEM], 58.7 [2.0] vs 47.5 [2.0]; P < .001) and abdominal insufflation (54.0 [2.0] vs 46.3 [2.0]; P = .002). There was no change in the instantaneous index after laryngoscopy (47.2 [2.2] vs 40.3 [2.3]; P = .026) and orogastric tube placement (49.8 [2.3] vs 45.4 [2.0]; P = .109). The instantaneous index increased after hydromorphone administration (58.2 [1.9] vs 64.8 [1.8]; P = .003). In adult subjects under general anesthesia for laparoscopic cholecystectomy, changes in the high-frequency HR variability index reflect alterations in the balance between nociception and analgesia. This index might be used intraoperatively to titrate analgesia for individual patients. Further testing is necessary to determine whether the intraoperative use of the index affects patient outcomes.

Pharmacokinetics of hydromorphone hydrochloride after intravenous and intramuscular administration in guinea pigs (Cavia porcellus).

To determine the pharmacokinetics of hydromorphone hydrochloride after IV and IM administration in guinea pigs (Cavia porcellus). 8 healthy adult guinea pigs (4 sexually intact females and 4 sexually intact males). In a crossover study, hydromorphone (0.3 mg/kg) was administered once IM (epaxial musculature) or IV (cephalic catheter) to each guinea pig at a 1-week interval (2 treatments/guinea pig). Blood samples were collected before and at predetermined intervals after drug administration via a vascular access port. Plasma hydromorphone concentrations were determined by liquid chromatography-tandem mass spectrometry. Noncompartmental analysis of data was used to calculate pharmacokinetic parameters. Mean ± SD clearance and volume of distribution for hydromorphone administered IV were 52.8 ± 13.5 mL/min/kg and 2.39 ± 0.479 L/kg, respectively. Mean residence time determined for the IV and IM administration routes was 0.77 ± 0.14 hours and 0.99 ± 0.34 hours, respectively. The maximum observed plasma concentration following IM administration of hydromorphone was 171.9 ± 29.4 ng/mL. No sedative effects were observed after drug administration by either route. Pharmacokinetic data indicated that hydromorphone at a dose of 0.3 mg/kg may be administered IV every 2 to 3 hours or IM every 4 to 5 hours to maintain a target plasma concentration between 2 and 4 ng/mL in guinea pigs. Hydromorphone had high bioavailability after IM administration. Further research is necessary to evaluate the effects of other doses and administration routes and the analgesic effects of hydromorphone in guinea pigs.

Opioid-induced Euphoria Among Emergency Department Patients With Acute Severe Pain: An Analysis of Data From a Randomized Trial.

Parenteral opioids are commonly used to treat acute severe pain. We measured pleasurable sensations in patients administered intravenous analgesics to determine if these sensations were associated with receipt of an opioid, after controlling for relief of pain. Pleasurable sensations not accounted for by relief of pain were considered opioid-induced euphoria. These data were from a randomized study of 1mg of hydromorphone versus 120mg of lidocaine for abdominal pain. To assess euphoria, participants were asked to provide a 0 to 10 response to each of these questions: 1) How good did the medication make you feel? 2) How high did the medication make you feel? and 3) How happy did the medication make you feel? Pain at baseline and 30minutes was also measured on a 0 to 10 scale. To determine the relative importance of pain relief versus medication type, we built three linear regression models in which each euphoria question was the dependent variable and pain relief, medication type, and medication-induced side effects were the independent variables. Seventy-seven patients received lidocaine and 77 hydromorphone. Hydromorphone patients reported greater pain improvement than lidocaine patients (mean difference=1.5, 95% confidence interval [CI]=0.6 to 2.3) and higher scores on all three euphoria questions ("feeling good" difference=1.9, 95% CI=0.8 to 3.0; "feeling high" difference=1.5, 95% CI=0.4 to 2.7; "feeling happy" difference=1.7, 95% CI=0.6 to 2.8). In the regression models, hydromorphone administration (β-coefficient=0.16, p=0.03) and pain relief (β-coefficient=0.45, p<0.01) were both associated with "feeling good." "Feeling high" and "feeling happy" were associated with pain improvement (p<0.01) but not with hydromorphone administration (p=0.07 for "high" and p=0.06 for "happy"). Medication-induced side effects were not associated with these measures of euphoria. Among emergency department patients with acute pain, hydromorphone-induced euphoria, though measurable, was generally less important for patients than relief of pain.

Individual differences in human opioid abuse potential as observed in a human laboratory study

BackgroundOpioids have high abuse potential and pose a major public health concern. Yet, a large percentage of individuals exposed to opioids do not develop problematic use. Individual differences in opioid abuse potential are not well understood. MethodsThis within-subject (N = 16), double-blind, double-dummy, human laboratory study evaluated individual differences in response to dose (placebo, low, medium, high) following administration of heroin and hydromorphone through intravenous and subcutaneous routes, in opioid-experienced but non physically-dependent participants. Outcomes were self-reported visual analog scale (VAS) ratings (High, Liking, Drug Effect, Good Effect, Rush), pupil diameter change from baseline, and crossover point on the Drug vs. Money questionnaire. The degree to which results were consistent across measures within an individual was assessed using a mixed-effects model from which an intraclass correlation coefficient measure of between and within-subject variance was derived. ResultsThe mixed effects model fit was significant (p < 0.0001) and revealed that 85.5% of the explainable variance was due to between-subject effects, suggesting the responses within an individual were highly consistent. Visual inspection reveals a myriad response pattern across participants, with some demonstrating classic dose-effect responses and others not differentiating any active doses from placebo. ConclusionsData suggest the abuse potential of opioids is significantly different between individuals but that the experience within an individual is highly consistent. Research to prospectively characterize and evaluate mechanisms underlying these differences is warranted and may provide a foundation to help identify persons at heightened risk of transitioning from opioid exposure to misuse and/or opioid use disorder.

A Randomized Controlled Trial to Compare Pain Medications in Children Undergoing Strabismus Surgery

The purpose of this study was to investigate optimal intraoperative combinations of analgesia for children undergoing strabismus surgery. A randomized controlled trial was employed to compare the difference in pain after administration of hydromorphone versus fentanyl. Participants were randomly assigned to either arm of the study. Pain was measured by the revised Faces, Legs, Activity, Cry, and Consolability Scale (rFLACC) tool postoperatively, and the parent was asked about the presence or absence of pain after discharge. A total of 135 children were included in the study. The rFLACC pain score was found to be significantly higher postoperatively among patients receiving fentanyl (P=.011). Pain after discharge was reported more often among patients who received fentanyl (P<.001). Results of this study can be used to change practice to minimize the pain levels both postoperatively and after discharge for children undergoing strabismus surgery.

Effects of anesthetic and sedative agents on sympathetic nerve activity

The effects of sedative and anesthetic agents on sympathetic nerve activity (SNA) are poorly understood. The purpose of this study was to determine the effects of commonly used sedative and anesthetic agents on SNA in ambulatory dogs and humans. We implanted radiotransmitters in 6 dogs to record stellate ganglion nerve activity (SGNA), subcutaneous nerve activity (ScNA), and blood pressure (BP). After recovery, we injected dexmedetomidine (3 μg/kg), morphine (0.1 mg/kg), hydromorphone (0.05 mg/kg), and midazolam (0.1 mg/kg) on different days. We also studied 12 human patients (10 male; age 68.0 ± 9.1 years old) undergoing cardioversion for atrial fibrillation with propofol (0.77 ± 0.18 mg/kg) or methohexital (0.65 mg/kg) anesthesia. Skin sympathetic nerve activity (SKNA) and electrocardiogram were recorded during the study. SGNA and ScNA were significantly suppressed immediately after administration of dexmedetomidine (P = .000 and P= .000, respectively), morphine (P = .011 and P = .014, respectively), and hydromorphone (P = .000 and P = .012, respectively), along with decreased BP and heart rate (HR) (P <.001 for each). Midazolam had no significant effect on SGNA and ScNA (P = .248 and P = .149, respectively) but increased HR (P = .015) and decreased BP (P = .004) in ambulatory dogs. In patients undergoing cardioversion, bolus propofol administration significantly suppressed SKNA (from 1.11 ± 0.25 μV to 0.77 ± 0.15 μV; P=.001), and the effects lasted for at least 10 minutes after the final cardioversion shock. Methohexital decreased chest SKNA from 1.59 ± 0.45 μV to 1.22 ± 0.58 μV (P = .000) and arm SKNA from 0.76 ± 0.43 μV to 0.55 ± 0.07 μV (P = .001). The effects lasted for at least 10 minutes after the cardioversion shock. Propofol, methohexital, dexmedetomidine, morphine, and hydromorphone suppressed, but midazolam had no significant effects on, SNA.

The antinociceptive effects of intravenous administration of three doses of butorphanol tartrate or naloxone hydrochloride following hydromorphone hydrochloride to healthy conscious cats

ObjectiveTo evaluate thermal antinociception from intravenous (IV) administration of hydromorphone alone or followed by butorphanol or naloxone in cats. Study designRandomized, controlled, masked, crossover design. AnimalsA group of eight adult female cats. MethodsCats were administered six treatments of two IV injections 30 minutes apart: treatments S–S, two 0.9% saline; H–S, hydromorphone (0.1 mg kg−1) and saline; H–LB, hydromorphone and butorphanol (0.02 mg kg−1); H–MB, hydromorphone and butorphanol (0.1 mg kg−1); H–HB, hydromorphone and butorphanol (0.2 mg kg−1); H–N, hydromorphone and naloxone (0.04 mg kg−1). Skin temperature (ST), thermal threshold (TT) and sedation score (SS) were recorded before (baseline) and for 8 hours after the first injection. Percentage maximum possible effect (%MPE), thermal excursion (TE), TT, SS and ST were compared using two-way repeated measures anova or Friedman test followed by Tukey’s or Dunn’s multiple comparisons test when appropriate. Significance was set at p ≤ 0.05. ResultsData from seven cats were analyzed. There were no significant differences among treatments in baseline values, SS and within S–S over time. Compared with respective 0.5 hour values following hydromorphone administration, %MPE was significantly lower at 4–8 hours for H–S; at 3–8 hours for H–LB; at 4–8 hours for H–MB; at 6–8 hours for H–HB and at 1–8 hours for H–N. Compared with respective 0.5 hour values, TE was significantly lower at 4–8 hours for H–S; at 3–8 hours for H–LB; at 2 and 4–8 hours for H–MB; at 6 and 8 hours for H–HB and at 1–8 hours for H–N. Conclusions and clinical relevanceButorphanol and naloxone reduced hydromorphone-induced thermal antinociception. Butorphanol preserved hydromorphone antinociceptive properties better than naloxone. Butorphanol is recommended during non-life-threatening scenarios as a partial reversal agent for hydromorphone in cats.