Paw placement during walking is altered by analgesic doses of opioids and post-surgical injury in mice

Hind paw-directed assays are commonly used to study the analgesic effects of opioids in mice. However, opioid-induced hyper-locomotion can obscure results of such assays. We aimed to overcome this potential confound by using gait analysis to observe hind paw usage during walking in mice. We measured changes in paw print area following induction of post-surgical pain (using the paw incision model) and treatment with oxycodone. Paw incision surgery reduced the paw print area of the injured hind paw as the mice avoided placing the incised section of the paw on the floor. Surprisingly, oxycodone caused a tiptoe-like gait in mice, resulting in a reduced paw print area in both hind paws. Further investigation of this opioid-induced phenotype revealed that analgesic doses of oxycodone or morphine dose-dependently reduced hind paw print area in uninjured mice. The gait changes were not dependent on opioid-induced increases in locomotor activity; speed and paw print area had no correlation in opioid-treated mice, and other analgesic compounds that alter locomotor activity did not affect paw print area. Unfortunately, the opioid-induced 'tiptoe' gait phenotype prevented gait analysis from being a viable metric for demonstrating opioid analgesia in injured mice. However, this work reveals an important, previously uncharacterized effect of treatment with analgesic doses of opioids on paw placement. Our characterization of how opioids affect gait has important implications for the use of mice to study opioid pharmacology and suggests that scientists should use caution when using hind paw-directed nociceptive assays to test opioid analgesia in mice.

Profiling the Effects of Repetitive Morphine Administration on Motor Behavior in Rats

Efficient repetitive clinical use of morphine is limited by its numerous side effects, whereas analgesic tolerance necessitates subsequent increases in morphine dose to achieve adequate levels of analgesia. While many studies focused on analgesic tolerance, the effect of morphine dosing on non-analgesic effects has been overlooked. This study aimed to characterize morphine-induced behavior and the development and progression of morphine-induced behavioral tolerance. Adult male Sprague–Dawley rats were repetitively treated with subcutaneous morphine for 14 days in two dose groups (A: 5 mg/kg/day (b.i.d.) → 10 mg/kg/day; B: 10 mg/kg/day (b.i.d.) → 20 mg/kg/day). Motor behavior was assessed daily (distance traveled, speed, moving time, rearing, rotation) in an open-field arena, before and 30 min post-injections. Antinociception was measured using tail-flick and hot-plate assays. All measured parameters were highly suppressed in both dosing groups on the first treatment day, followed by a gradual manifestation of behavioral tolerance as the treatment progressed. Animals in the high-dose group showed increased locomotor activity after 10 days of morphine treatment. This excitatory phase converted to an inhibition of behavior when a higher morphine dose was introduced. We suggest that the excitatory locomotor effects of repetitive high-dose morphine exposure represent a signature of its behavioral and antinociceptive tolerance.

An opioid-sparing protocol with intravenous parecoxib can effectively reduce morphine consumption after simultaneous bilateral total knee arthroplasty

Multimodal pain management protocol effectively relieves pain following simultaneous bilateral total knee arthroplasty (SBTKA) but is associated with administration of large amounts of opioids in the perioperative period. In this prospective, randomized, assessor-blinded, single-surgeon clinical trial, the goal was to validate the efficacy of an opioid-sparing protocol for SBTKA with a reduced opioid dose, while achieving similar pain relief with few adverse events. Fifty-six patients who had undergone SBTKA were randomly allocated to receive either an opioid-sparing or opioid-based protocol. The primary outcome parameters were visual analogue scale (VAS) scores at rest, with movement, and cumulative morphine dose, through time. Secondary outcome parameters included drug-related adverse events and range of motion with continuous passive motion device, through time. In the opioid-sparing group, a lower VAS score with movement at postoperative 24 and 72 h was observed compared with the opioid-based group, but the difference did not reach the minimal clinically importance difference. A reduced cumulative morphine dose was noted in the opioid-sparing group at postoperative 24, 48 and 72 h. In conclusion, the opioid-sparing protocol may be used as an alternative modality for pain management following SBTKA. Similar pain relief effects may be achieved utilizing a reduced cumulative opioid dose, with few opioid related adverse events.

Is Maternal Methadone Dose Associated with the Severity of Neonatal Abstinence Syndrome?

Objective The aim of the study is to assess the correlation between maternal methadone dose and severity of neonatal abstinence syndrome (NAS) in infants that required pharmacological treatment for NAS. Study Design This is a retrospective analysis of 574 infants ≥35 weeks' gestation exposed to methadone in utero, born between August 2006 and May 2018, and who required pharmacological therapy for NAS. Indicators of NAS severity (duration of morphine treatment, maximum morphine dose, use of phenobarbital, and length of hospitalization) were compared between infants exposed to high (≥200 mg), intermediate (100–199 mg), and low doses (<100 mg) of methadone. Logistic and linear regression models were used to adjust for the covariates. Results Median (interquartile range) duration of medical treatment with morphine was higher in infants exposed to higher doses of methadone (low dose 23 [14–37] days, intermediate dose 31 [18–45] days, and high dose 35 [20–48] days, p < 0.001). Higher methadone doses were also predictive of longer duration of hospitalization, higher maximum morphine dose, and increased likelihood of treatment with phenobarbital. The association between maternal methadone dose and the severity of NAS persisted in multivariable regression models. Conclusion Infants exposed to higher methadone doses displayed more severe NAS, as indicated by longer durations of treatment, higher maximum morphine dose, longer duration of hospitalization, and increased likelihood of phenobarbital use. Key Points

Evaluation of the Efficacy of Low-Dose Naloxone for the Prevention of Acute Remifentanil-Induced Hyperalgesia in Patients Undergoing General Anesthesia for Laparotomy

Background: Hyperalgesia is a major complication of continuous or intermittent opioid administration. The evidence suggests that concomitant administration of low-dose naloxone could prevent the development of acute opioid-induced hyperalgesia, with no effect on pain control. Objectives: The current study aimed to assess the effects of intraoperative low-dose naloxone, adding to remifentanil infusion on preventing acute postoperative hyperalgesia in patients undergoing general anesthesia for laparotomy. Methods: In this randomized clinical trial, patients undergoing general anesthesia for laparotomic hysterectomy in a tertiary referral teaching hospital from February to December 2019 were randomly assigned to one of three groups of remifentanil-naloxone (remifentanil 0.3 μg/ kg/min with low-dose naloxone 0.25μg/kg /h prepared in 50 mL of normal saline), remifentanil (0.3 μg/kg/min), and control (receiving 50 mL saline infusion), intraoperatively. Patients and researchers were blinded to the type of intervention. The severity of hyperalgesia, as the main outcome, was evaluated by the static Tactile test. The severity of pain was assessed by visual analogous scale 0.5, 2, 6, 12, and 24 hours after surgery. Results: In total, 75 patients were evaluated. The results showed no difference concerning the independent variables (age, body mass index, hypertension, surgery duration, anesthesia duration, and American Society of Anesthesiologists (ASA) class) between the three groups. Heart rate was significantly different in all study time points between the three groups (P < 0.001), but mean arterial pressure and systolic and diastolic blood pressure showed no significant difference (P > 0.05) throughout the study. Assessment of hyperalgesia using the tactile test revealed a higher incidence of hyperalgesia in the remifentanil group in 0.5, 2, 6, 12, and 24 hours after surgery compared to the other two groups, which was statistically significant between the groups at 0.5, 2, and 6 hours after surgery (P < 0.05). Shivering incidence, Morphine dose in 24 hours post-surgery, morphine dose in the recovery room, and VAS for pain were significantly different during the study between the three groups (P < 0.05). Conclusions: This study demonstrated the efficacy of intraoperative low-dose naloxone (0.25 μg/kg/h) added to remifentanil infusion on reducing the frequency and severity of acute postoperative hyperalgesia in patients undergoing general anesthesia for laparotomy hysterectomy.