Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs

The safe disposal of unused opioid drugs is an area of regulatory concern. While toilet flushing is recommended for some drugs to prevent accidental exposure, there is a need for data that can support a more consistent disposal policy based on an assessment of relative risk. For drugs acting at the Mu-opioid receptor (MOR), published measurements of binding affinity (K(i)) are incomplete and inconsistent due to differences in methodology and assay system, leading to a wide range of values for the same drug thus precluding a simple and meaningful relative ranking of drug potency. Experiments were conducted to obtain K(i)'s for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. The K(i) values obtained ranged from 0.1380 nM (sufentanil) to 12.486 μM (tramadol). The drugs were separated into three categories based upon their K(i) values: K(i) > 100 nM (tramadol, codeine, meperidine, propoxyphene and pentazocine), K(i)=1-100 nM (hydrocodone, oxycodone, diphenoxylate, alfentanil, methadone, nalbuphine, fentanyl and morphine) and K(i) < 1 nM (butorphanol, levorphanol, oxymorphone, hydromorphone, buprenorphine and sufentanil). These data add to the understanding of the pharmacology of opioid drugs and support the development of a more consistent labeling policies regarding safe disposal.     

Delay discounting, impulsiveness, and addiction severity in opioid-dependent patients

Individuals who abuse drugs show higher delay discounting (DD) rate and impulsiveness scores compared with controls; however, it is unclear if DD rate covaries with severity of the addiction or if an individual's discounting rate can be changed by effective substance abuse treatment. This study compared methadone maintenance treatment (MMT) patients (n = 30) who had not used illegal drugs for 2 years with drug-using MMT patients (n = 30) and controls (n = 25) in terms of addiction severity, DD rate, and impulsiveness. Methadone patients abstinent from illegal drugs scored significantly lower on a number of addiction severity measures than the drug-using methadone patients. In addition, both groups of MMT patients showed significantly higher rates of DD and impulsiveness than the control group; however, no differences in DD rate or impulsiveness were found between the groups of patients. Results suggest that DD rate and impulsiveness may not covary with indicators of addiction severity in MMT patients.     

Comparative patterns of cognitive performance amongst opioid maintenance patients,abstinent opioid users and non-opioid users

Background

To compare the cognitive performances of maintenance patients (MAIN), abstinent ex-users (ABST) and healthy non-heroin using controls (CON).

Methods

Case control study of 125 MAIN (94 subjects maintained on methadone, 31 on buprenorphine), 50 ABST and 50 CON. Neuropsychological tests measuring executive function, working memory, information processing speed, verbal learning and non-verbal learning were administered.

Results

There were no differences between the cognitive profiles of those maintained on methadone or buprenorphine on any administered test. After controlling for confounders, the MAIN group had poorer performance than controls in six of the 13 administered tests, and were poorer than the ABST group in five. The MAIN group exhibited poorer performance in the Haylings Sentence Completion, Matrix Reasoning, Digit Symbol, Logical Memory (immediate and delayed recall), and the Complex Figure Test (immediate recall). There were no differences between the ABST and CON groups on any of the administered tests.

Conclusions

Poorer cognitive performance, across a range of test and domains, was seen amongst maintenance patients, regardless of their maintenance drug. This is a group that is likely might benefit from approaches for managing individuals with cognitive and behavioural difficulties arising from brain dysfunction.     

Long-term gender behavioral vulnerability after nociceptive neonatal formalin stimulation in rats

d-Cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine recognition site on the N-methyl-d-aspartate (NMDA) receptor complex, has been shown to facilitate the extinction and prevent the relapse of cocaine-induced conditioned place preference (CPP) when administered before or after each extinction trail. However, some studies have suggested that DCS does not influence or even enhance relapse of seeking behavior on cocaine self-administration (SA) in rats or cocaine-dependent individuals undergoing clinical exposure treatment. Furthermore, there are no reports on the effects of DCS and the extinction of morphine-conditioned behaviors in mice. The present study investigated the effects of DCS on extinction by exposing mice to drug-paired cues and the subsequent reinstatement of morphine-primed CPP. Our results showed that DCS at doses of 7.5, 15, and 30 mg/kg did not induce conditioned appetitive or aversive effects and DCS combined with morphine conditioning failed to affect the acquisition of morphine-induced CPP. Moreover, pretreatment with DCS (7.5, 15, and 30 mg/kg, i.p.) prior to extinction training had no significant effects on the extinction and subsequent morphine-primed reinstatement of morphine-induced CPP. These results suggested that DCS may not be a powerful adjunct for cue exposure therapy of opioid addiction. In view of differing outcomes in both preclinical and clinical studies, the potential of DCS in exposure treatment of drug-seeking behaviors should be carefully evaluated.     

Can intravenous lidocaine decrease postsurgical ileus and shorten hospital stay in elective bowel surgery? A pilot study and literature review

Background

This study examined whether systemic infusion of lidocaine, a local anesthetic with anti-inflammatory properties, can decrease surgical pain, length of postsurgical ileus, and hospital stay.

Methods

Twenty-two patients at a community hospital were randomized into 2 groups. Subjects were allocated to receive either lidocaine or a placebo infusion for the first 24 hours after surgery.

Results

Patients in the lidocaine group appeared to report less pain as reflected by a decrease in overall visual analogue scale pain scores 24 hours after surgery. The return of flatus after surgery was not considered significant (lidocaine 68.2 ± 9.7 hours vs placebo 86.9 ± 13.6 hours; P = .2802). The return of bowel movement after surgery was considered significant (lidocaine 88.3 ± 6.08 hours vs placebo group 116 ± 10.1 hours; P = .0286). The lidocaine group was discharged by mean day 3.76 ± .24 versus placebo at mean day 4.93 ± .42; P = .0277.

Conclusions

Patients in the lidocaine group had bowel movements >24 hours earlier than those in the placebo group and were discharged earlier.     

Psychiatrists as Administrators: The Perspective of a Mental Health Department Psychiatrist

This paper is adapted from the American Association of Psychiatric Administrators Annual Membership Luncheon Speech given at the meeting of the American Psychiatric Association in Toronto, Canada on May 23, 2006. The author discusses three experiences from his work for the New York City Department of Health and Mental Hygiene to illustrate how psychiatrists working as administrators are uniquely able to meet community mental health and substance misuse needs. The author describes public health interventions employed by psychiatric administrators to reduce morbidity and mortality from opioid and methamphetamine misuse. Presented at the Annual Meeting of the American Association of Psychiatric Administrators, Toronto, Canada, May 23, 2006.     

Role of active metabolites in the use of opioids

The opioid class of drugs, a large group, is mainly used for the treatment of acute and chronic persistent pain. All are eliminated from the body via metabolism involving principally CYP3A4 and the highly polymorphic CYP2D6, which markedly affects the drug’s function, and by conjugation reactions mainly by UGT2B7. In many cases, the resultant metabolites have the same pharmacological activity as the parent opioid; however in many cases, plasma metabolite concentrations are too low to make a meaningful contribution to the overall clinical effects of the parent drug. These metabolites are invariably more water soluble and require renal clearance as an important overall elimination pathway. Such metabolites have the potential to accumulate in the elderly and in those with declining renal function with resultant accumulation to a much greater extent than the parent opioid. The best known example is the accumulation of morphine-6-glucuronide from morphine. Some opioids have active metabolites but at different target sites. These are norpethidine, a neurotoxic agent, and nordextropropoxyphene, a cardiotoxic agent. Clinicians need to be aware that many opioids have active metabolites that will become therapeutically important, for example in cases of altered pathology, drug interactions and genetic polymorphisms of drug-metabolizing enzymes. Thus, dose individualisation and the avoidance of adverse effects of opioids due to the accumulation of active metabolites or lack of formation of active metabolites are important considerations when opioids are used.     

Opioid-induced respiratory depression and risk factors in a tertiary hospital: A retrospective study

BackgroundOpioids are potent analgesics used for the treatment of moderate to severe acute and chronic cancer and non-cancer pain. However, opioid usage may be limited by negative side effects, such as potentially life-threatening respiratory depression.ObjectivesThe aim of our study is to investigate the prevalence of opioid-induced respiratory depression (OIRD) and its predictors at King Abdulaziz Medical City in Jeddah (KAMC-JD).MethodThis is a retrospective cross-sectional (chart review) study conducted from January 1, 2016, to December 31, 2020.ResultsA total of 15,753 patients received opioids during admission to KAMC-JD, and only 144 (0.915%) of them received naloxone from January 1, 2016 to December 31, 2020. Only 91 patients (0.57%) developed opioid-induced respiratory depression (OIRD), which was more frequently reported among young and middle-aged adults. OIRD was significantly associated with receiving a daily morphine milligram equivalent (MME) dose of ≥150 MME and with having a low urea concentration at the baseline and at admission under surgery. Also, fentanyl use remained a significant risk factor for OIRD.ConclusionIn conclusion, monitoring patient receiving opioids with a daily MME dose of ≥150 MME, prescribed Fentanyl, low urea concentration at the baseline, and patients’ admissions to the surgery department may mitigate the risk of developing OIRD.