Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D₃ receptor (D₃R) have effects on addiction in different animal models. We have previously reported that YQA14, a D₃R antagonist, exhibits very high affinity and selectivity for D₃Rs over D₂Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D₃R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.
Rats ; Mice ; Animals ; Analgesics, Opioid ; Dopamine ; Heroin/pharmacology* ; Dopamine Antagonists/pharmacology* ; Receptors, Dopamine D3/metabolism* ; Morphine/pharmacology* ; Behavior, Addictive/drug therapy* ; Self Administration

Preclinical studies suggest that the GABA receptor is a potential target for treatment of substance use disorders. Baclofen (BLF), a prototypical GABA receptor agonist, is the only specific GABA receptor agonist available for application in clinical addiction treatment. The nucleus accumbens shell (AcbSh) is a key node in the circuit that controls reward-directed behavior. However, the relationship between GABA receptors in the AcbSh and memory reconsolidation was unclear. The aim of this study was to investigate the effect of intra-AcbSh injection of BLF on the reconsolidation of morphine reward memory. Male C57BL/6J mice were used to establish morphine conditioned place preference (CPP) model and carry out morphine reward memory retrieval and activation experiment. The effects of intra-AcbSh injection of BLF on morphine-induced CPP, reinstatement of CPP and locomotor activity were observed after environmental cues activating morphine reward memory. The results showed that intra-AcbSh injection of BLF (0.06 nmol/0.2 μL/side or 0.12 nmol/0.2 μL/side), rather than vehicle or BLF (0.01 nmol/0.2 μL/side), following morphine reward memory retrieval abolished morphine-induced CPP by disrupting its reconsolidation in mice. Moreover, this effect persisted for more than 14 days, which was not reversed by a morphine priming injection. Furthermore, intra-AcbSh injection of BLF without morphine reward memory retrieval had no effect on morphine-associated reward memory. Interestingly, administration of BLF into the AcbSh had no effect on the locomotor activity of mice during testing phase. Based on these results, we concluded that intra-AcbSh injection of BLF following morphine reward memory could erase morphine-induced CPP by disrupting its reconsolidation. Activating GABA receptor in AcbSh during drug memory reconsolidation may be a potential approach to prevent drug relapse.
Animals ; Baclofen ; administration & dosage ; Conditioning, Classical ; GABA-B Receptor Agonists ; administration & dosage ; Locomotion ; Male ; Memory ; Mice ; Mice, Inbred C57BL ; Morphine ; Nucleus Accumbens ; drug effects ; Opioid-Related Disorders ; Reward

INTRODUCTION: Adductor canal block (ACB) is hypothesised to provide superior analgesia to femoral nerve block (FNB) for total knee arthroplasty (TKA) while preserving quadriceps strength. METHODS: 30 patients undergoing TKA were randomised to receive either ACB or FNB. Baseline tests of quadriceps strength were performed. Ultrasound-guided blocks with 30 mL of 0.5% ropivacaine were administered before induction of general anaesthesia. Patient-controlled analgesia (morphine) was prescribed for postoperative analgesia. The primary outcome of this prospective, double-blinded, randomised controlled trial was morphine consumption (mean ± standard deviation) in the first 24 hours. Secondary outcomes were pain scores using a numeric rating scale (median and interquartile range [IQR]), quadriceps strength (% of baseline) and functional outcomes at 24 hours and 48 hours postoperatively. RESULTS: There was no statistically significant difference in morphine consumption at 24 hours between the ACB and FNB groups (21 ± 11 mg vs. 20 ± 12 mg; p = 0.85). No statistically significant differences were observed between the ACB and FNB groups in pain scores at 24 hours (at rest: 0 [IQR 0-2] vs. 0 [IQR 0-2]; on movement: 5 [IQR 4-8] vs. 5 [IQR 3-8]) and quadriceps strength (24 hours: 28.8% ± 26.1% vs. 26.8% ± 19.6% of baseline; 48 hours: 31.5 ± 23.1% vs. 33.7% ± 20.1% of baseline). There were also no statistically significant differences in functional outcomes and length of stay. CONCLUSION We found no statistically significant differences in analgesic effects, quadriceps strength or functional recovery postoperatively between ACB and FNB.
Aged ; Aged, 80 and over ; Analgesia, Patient-Controlled ; methods ; Analgesics, Opioid ; therapeutic use ; Anesthetics, Local ; administration & dosage ; Arthroplasty, Replacement, Knee ; Double-Blind Method ; Female ; Femoral Nerve ; Humans ; Male ; Middle Aged ; Morphine ; therapeutic use ; Nerve Block ; methods ; Pain Management ; methods ; Pain Measurement ; Pain, Postoperative ; drug therapy ; Prospective Studies ; Quadriceps Muscle ; drug effects ; Treatment Outcome ; Ultrasonography

BACKGROUND: Patient-controlled epidural analgesia (PCEA) is known to provide good postoperative analgesia in many types of surgery including laparoscopic surgery. However, no study has compared PCEA with patient-controlled intravascular analgesia (PCIA) in laparoscopic radical prostatectomy (LARP). In this study, the efficacy and side effects of PCEA and PCIA after LARP were compared. METHODS: Forty patients undergoing LARP were randomly divided into two groups: 1) a PCEA group, treated with 0.2% ropivacaine 3 ml and 0.1 mg morphine in the bolus; and 2) a PCIA group, treated with oxycodone 1 mg and nefopam 1 mg in the bolus. After the operation, a blinded observer assessed estimated blood loss (EBL), added a dose of rocuronium, performed transfusion, and added analgesics. The numeric rating scale (NRS), infused PCA dose, and side effects were assessed at 1, 6, 24, and 48 h. RESULTS: EBL, added rocuronium, and added analgesics in the PCEA group were less than those in the PCIA group. There were no significant differences in side-effects after the operation between the two groups. Patients were more satisfied with PCEA than with PCIA. The NRS and accumulated PCA count were lower in PCEA group. CONCLUSIONS: Combined thoracic epidural anesthesia could induce less blood loss during operations. PCEA showed better postoperative analgesia and greater patient satisfaction than PCIA. Thus, PCEA may be a more useful analgesic method than PICA after LARP.
Administration, Intravenous ; Analgesia ; Analgesia, Epidural ; Analgesia, Patient-Controlled ; Analgesics ; Anesthesia, Epidural ; Humans ; Injections, Epidural ; Laparoscopes ; Laparoscopy ; Methods ; Morphine ; Nefopam ; Oxycodone ; Pain Measurement ; Pain, Postoperative ; Passive Cutaneous Anaphylaxis ; Patient Satisfaction ; Pica ; Prostatectomy ; Thoracic Vertebrae

PURPOSE: Intrathecal morphine pump (ITMP) infusion therapy is efficient in managing malignant and nonmalignant chronic pain refractory to standard treatment. However, the high cost of an ITMP is the greatest barrier for starting a patient on ITMP infusion therapy. Using the revised Korean reimbursement guidelines, we investigated the cost effectiveness of ITMP infusion therapy and conducted a patient survey. MATERIALS AND METHODS: A retrospective chart review of 12 patients who underwent ITMP implantation was performed. Morphine dose escalation rates were calculated, and numeric rating scale (NRS) scores were compared before and after ITMP implantation. We surveyed patients who were already using an ITMP as well as those who were candidates for an ITMP. All survey data were collected through in-person interviews over 3 months. Data on the cost of medical treatment were collected and projected over time. RESULTS: The NRS score decreased during the follow-up period. The median morphine dose increased by 36.9% over the first year, and the median time required to reach a financial break-even point was 24.2 months. Patients were more satisfied with the efficacy of ITMP infusion therapy than with conventional therapy. The expected cost of ITMP implantation was KRW 4000000-5000000 in more than half of ITMP candidates scheduled to undergo implantation. CONCLUSION: The high cost of initiating ITMP infusion therapy is challenging; however, the present results may encourage more patients to consider ITMP therapy.
Adult ; Aged ; Analgesics, Opioid/*administration & dosage/economics/therapeutic use ; Chronic Pain/*drug therapy ; Cost-Benefit Analysis ; Female ; Humans ; Infusion Pumps, Implantable/*economics ; Injections, Spinal ; Male ; Middle Aged ; Morphine/*administration & dosage/economics/therapeutic use ; Pain Management/*methods/trends ; Patient Satisfaction ; Republic of Korea ; Retrospective Studies ; Surveys and Questionnaires ; Treatment Outcome

BACKGROUND: Postoperative pain relief can be achieved with various modalities. However, there are only few reports that have analyzed postoperative analgesic techniques in total hip arthroplasty patients. The aim of this retrospective study was to compare the postoperative outcomes of three different analgesic techniques after total hip arthroplasty. METHODS: We retrospectively reviewed the influence of three analgesic techniques on postoperative rehabilitation after total hip arthroplasty in 90 patients divided into three groups (n = 30 patients per group). Postoperative analgesia consisted of continuous epidural analgesia (Epi group), patient-controlled analgesia with morphine (PCA group), or a continuous femoral nerve block (CFNB group). We measured the following parameters relating to postoperative outcome: visual analog scale scores, the use of supplemental analgesia, side effects, length of the hospital stay, plasma D-dimer levels, and the Harris hip score. RESULTS: Each group had low pain scores with no significant differences between the groups. The PCA group had a lower frequency of supplemental analgesia use compared to the Epi and CFNB groups. Side effects (nausea/vomiting, inappetence) and day 7 D-dimer levels were significantly lower in the CFNB group (p < 0.05). There were no significant differences between the groups in terms of the length of the hospital stay or the Harris hip score. CONCLUSIONS: Although there were no clinically significant differences in outcomes between the three groups, the CFNB provided good pain relief which was equal to that of the other analgesics with fewer side effects and lower D-dimer levels in hospitalized patients following total hip arthroplasty.
Adult ; Aged ; Aged, 80 and over ; *Analgesia, Epidural/methods ; *Analgesia, Patient-Controlled ; Analgesics, Opioid/*administration & dosage ; *Arthroplasty, Replacement, Hip ; Female ; *Femoral Nerve ; Fibrin Fibrinogen Degradation Products/analysis ; Humans ; Length of Stay ; Male ; Middle Aged ; Morphine/*administration & dosage ; *Nerve Block/methods ; Pain, Postoperative/*prevention & control ; Retrospective Studies ; Treatment Outcome

PURPOSE: Epidural analgesia has been the preferred analgesic technique after major abdominal surgery. On the other hand, the combined use of intrathecal morphine (ITM) and intravenous patient controlled analgesia (IVPCA) has been shown to be a viable alternative approach for analgesia. We hypothesized that ITM combined with IVPCA is as effective as patient controlled thoracic epidural analgesia (PCTEA) with respect to postoperative pain control after conventional open gastrectomy. MATERIALS AND METHODS: Sixty-four patients undergoing conventional open gastrectomy due to gastric cancer were randomly allocated into the intrathecal morphine combined with intravenous patient-controlled analgesia (IT) group or patient-controlled thoracic epidural analgesia (EP) group. The IT group received preoperative 0.3 mg of ITM, followed by postoperative IVPCA. The EP group preoperatively underwent epidural catheterization, followed by postoperative PCTEA. Visual analog scale (VAS) scores were assessed until 48 hrs after surgery. Adverse effects related to analgesia, profiles associated with recovery from surgery, and postoperative complications within 30 days after surgery were also evaluated. RESULTS: This study failed to demonstrate the non-inferiority of ITM-IVPCA (n=29) to PCTEA (n=30) with respect to VAS 24 hrs after surgery. Furthermore, the IT group consumed more fentanyl than the EP group did (1247.2+/-263.7 microg vs. 1048.9+/-71.7 microg, p<0.001). The IT group took a longer time to ambulate than the EP group (p=0.021) and had higher incidences of postoperative ileus (p=0.012) and pulmonary complications (p=0.05) compared with the EP group. CONCLUSION: ITM-IVPCA is not as effective as PCTEA in patients undergoing gastrectomy, with respect to pain control, ambulation, postoperative ileus and pulmonary complications.
Adult ; Analgesia, Epidural/*methods ; Analgesia, Patient-Controlled/methods ; Analgesics, Opioid/administration & dosage/therapeutic use ; Female ; Gastrectomy/*methods ; Humans ; Male ; Middle Aged ; Morphine/*administration & dosage/*therapeutic use ; Pain Management/methods ; Pain, Postoperative/*drug therapy

Agmatine ; administration & dosage ; pharmacology ; Analgesia ; methods ; Animals ; Injections, Spinal ; Male ; Morphine ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; drug effects

OBJECTIVETo study and compare the effect of Corydalis yanhusuo and L-THP on dopamine neurotransmitter and D2 receptor of reward circuitry in various cerebral areas of conditioned place preference model rats and the comparison of their effects.

METHODThe CPP model was established by injecting morphine in rats with increasing doses for 10 days. The initial dose of 10 mg x kg(-1), and the final dose of 100 mg x kg(-1), with 10 mg x kg(-1) increased each day. At 48 h after the final training, CPP was adopted to detect the successful establishment of the model. On the same day (12 d), they were orally administered with 2, 1, 0.5 g x kg(-1) C. yanhusuo (containing 0.153, 0.077 and 0.038 mg L-THP) and L-THP (3.76, 1.88, 0.94 mg x kg(-1)) for six days. On 18 d, CPP test was performed again. Next day, HPLC was adopted to determine the content of dopamine neurotransmitters of reward circuitry in VTA-NAc-PFC; Immunohistochemistry and Western blotting were adopted to detect the expression of D2 receptors.

RESULTCompared with the physiological saline treatment group, C. yanhusuo (2, 1 g x kg(-1)) and L-THP (3.76, 1.88 mg x kg(-1)) groups showed that rats stayed in a notably shorter period in white boxes (morphine-accompanied boxes) (P < 0.01 or P < 0.05), and revealed a remarkably lower dopamine content in VTA, NAc and PFC and the significant increase in the expression of D2 receptor (P < 0.01 or P < 0.05).

CONCLUSIONThe down-regulation of the increased dopamine content in reward nervous circuitry and the up-regulation of the expression of D2 receptor may be one of mechanisms of C. yanhusuo and L-THP in accelerating the recession of morphine's CPP effect Regarding the inhibition of morphine's CPP effect and the effect on dopamine system, the effect of C. yanhusuo traditional Chinese medicine containing one-fold L-THP monomer is equal to that of the independent application of around 24-fold L-THP monomer.

Animals ; Berberine Alkaloids ; administration & dosage ; Brain ; drug effects ; metabolism ; physiopathology ; Conditioning, Operant ; drug effects ; Corydalis ; chemistry ; Dopamine ; metabolism ; Humans ; Male ; Morphine ; adverse effects ; Plant Extracts ; administration & dosage ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine D2 ; genetics ; metabolism ; Substance-Related Disorders ; drug therapy ; genetics ; metabolism ; psychology

BACKGROUND: Intravenous patient controlled analgesia (IV-PCA) is a most common used delivery system for intravenous administration of opioids during acute post operative pain management. The objective of this study is to compare the rate of opioid induced adverse reactions and effectiveness among two IV-PCA opioids, morphine, fentanyl, in laparoscopic cholecystectomy pain management. METHODS: Sixty patients in ASA physical status 1 and 2 scheduled for laparoscopic cholecystectomy were allocated randomly to either morphine IV-PCA used (n = 30, Group M) group or fentanyl IV-PCA used (n = 30, Group F) group. In each group, numerical rating scale (NRS) score, sedation score and incidence of side effect were checked. RESULTS: NRS score of Group F showed lower than that of Group M during PACU and 3 hrs after the recovery room (P < 0.05). There were no significant differences in sedation score among two groups. The incidences of adverse reactions were similar in the two groups, though the incidence of nausea and pruritus were higher in the Group M. CONCLUSIONS: Fentanyl IV-PCA is more advantageous than morphine IV-PCA for laparoscopic cholecystectomy in view of early pain control and adverse reaction incidences.
Administration, Intravenous ; Analgesia, Patient-Controlled ; Analgesics, Opioid ; Cholecystectomy, Laparoscopic ; Fentanyl ; Humans ; Incidence ; Morphine ; Nausea ; Pain Management ; Pruritus ; Recovery Room