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OPRM1 rs1799971 polymorphism and opioid dependence: evidence from a meta-analysis

Haerian BS, Haerian MS

Pharmacogenomics, 2013 May;14(7):813-24.
PMID: 23651028 DOI: 10.2217/pgs.13.57

The OPRM1 gene encodes the µ-opioid receptor, which is the primary site of action of most opioids. Several studies and three meta-analyses have examined a possible link between the exonic OPRM1 A118G (rs1799971) polymorphism and opioid dependence; however, results have been inconclusive. Therefore, a systematic review and meta-analysis have been carried out to examine whether this polymorphism is associated with opioid dependence. Thirteen studies (n = 9385), comprising 4601 opioid dependents and 4784 controls, which evaluated association of the OPRM1 rs1799971 polymorphism with susceptibility to opioids, were included in this study. Our meta-analysis showed significant association between this polymorphism and susceptibility to opioid dependence in overall studies under a codominant model, as well as susceptibility to opioid dependence or heroin dependence in Asians under an autosomal dominant model. The nonsynonymous OPRM1 rs1799971 might be a risk factor for addiction to opioids or heroin in an Asian population.

Matched MeSH terms: Analgesics, Opioid/adverse effects
Self-reported prevalence and severity of opioid and kratom (Mitragyna speciosa korth.) side effects

Saref A, Suraya S, Singh D, Grundmann O, Narayanan S, Swogger MT, et al.

J Ethnopharmacol, 2019 Jun 28;238:111876.
PMID: 31014959 DOI: 10.1016/j.jep.2019.111876

ETHNOPHARMACOLOGICAL RELEVANCE: Mitragyna speciosa (Korth.) is a traditional medicinal plant widely used in Southeast Asia for its opioid-like effects. Although kratom produces analgesia through binding of mitragynine and other alkaloids at the mu-opioid receptor (MOR), the association of long-term kratom use with adverse opioid-like effects remains unknown.
AIM OF THE STUDY: To determine the self-reported prevalence and severity of opioid-related adverse effects after kratom initiation in a cohort of illicit opioid users.
MATERIALS AND METHODS: A total of 163 illicit opioid users with current kratom use history were recruited through convenience sampling from the northern states of Peninsular Malaysia. Face-to-face interviews were conducted using a semi-structured questionnaire.
RESULTS: Respondents were all males, majority Malays (94%, n = 154/163), with a mean age of 37.10 years (SD = 10.9). Most were single (65%, n = 106/163), had 11 years of education (52%, n = 85/163) and employed (88%, n = 144/163). Half reported using kratom for over >6 years (50%, n = 81/163), and 41% consumed >3 glasses of kratom daily (n = 67/163). Results from Chi-square analysis showed kratom initiation was associated with decreased prevalence of respiratory depression, constipation, physical pain, insomnia, depression, loss of appetite, craving, decreased sexual performance, weight loss and fatigue.
CONCLUSIONS: Our findings indicate that kratom initiation (approximately 214.29 mg of mitragynine) was associated with significant decreases in the prevalence and severity of opioid adverse effects.

Matched MeSH terms: Analgesics, Opioid/adverse effects*
The effect of intravenous magnesium on postoperative morphine consumption in noncardiac surgery: A systematic review and meta-analysis with trial sequential analysis

Ng KT, Yap JLL, Izham IN, Teoh WY, Kwok PE, Koh WJ

Eur J Anaesthesiol, 2020 Mar;37(3):212-223.
PMID: 31977626 DOI: 10.1097/EJA.0000000000001164

BACKGROUND: Several studies suggest that systemic magnesium reduces postoperative opioid consumption and the intensity of pain, but others report conflicting results. The efficacy and safety profile of intravenous magnesium in noncardiac surgery remain uncertain.
OBJECTIVES: The aim of this review was to investigate the effect of intravenous magnesium on the consumption of postoperative morphine in the first 24 h in adults undergoing noncardiac surgery.
DESIGN: Systematic review and meta-analysis with trial sequential analysis.
DATA SOURCES: MEDLINE, EMBASE, CENTRAL from their inception until January 2019.
ELIGIBILITY CRITERIA: All randomised clinical trials comparing intravenous magnesium versus placebo in noncardiac surgery were systematically searched in the databases. Observational studies, case reports, case series and nonsystematic reviews were excluded.
RESULTS: Fifty-one trials (n=3311) were included for quantitative meta-analysis. In comparison with placebo, postoperative morphine consumption at 24-h was significantly reduced in the magnesium group, with a mean difference [95% confidence interval (CI)] of -5.6 mg (-7.54 to -3.66, P

Matched MeSH terms: Analgesics, Opioid/adverse effects
Fulltext Early Initiation of Amphetamine-Type Stimulants (ATS) Use Associated with Lowered Cognitive Performance among Individuals with Co-Occurring Opioid and ATS Use Disorders in Malaysia

Chooi WT, Mohd Zaharim N, Desrosiers A, Ahmad I, Yasin MAM, Syed Jaapar SZ, et al.

J Psychoactive Drugs, 2017 06 29;49(4):326-332.
PMID: 28661714 DOI: 10.1080/02791072.2017.1342152

Amphetamine-type stimulants (ATS) use is increasingly prevalent in Malaysia, including among individuals who also use opioids. We evaluated cognitive functioning profiles among individuals with co-occurring opioid and ATS dependence and their lifetime patterns of drug use. Participants (N = 50) enrolling in a clinical trial of buprenorphine/naloxone treatment with or without atomoxetine completed the Raven's Standard Progressive Matrices, Rey-Osterrieth Complex Figure Test, Digit Span, Trail Making and Symbol Digit Substitution tasks. Multidimensional scaling and a K-means cluster analyses were conducted to classify participants into lower versus higher cognitive performance groups. Subsequently, analyses of variance procedures were conducted to evaluate between group differences on drug use history and demographics. Two clusters of individuals with distinct profiles of cognitive performance were identified. The age of ATS use initiation, controlling for the overall duration of drug use, was significantly earlier in the lower than in the higher cognitive performance cluster: 20.9 (95% CI: 18.0-23.8) versus 25.2 (95% CI: 22.4-28.0, p = 0.038). While adverse effects of ATS use on cognitive functioning can be particularly pronounced with younger age, potentially related to greater vulnerability of the developing brain to stimulant and/or neurotoxic effects of these drugs, the current study findings cannot preclude lowered cognitive performance before initiation of ATS use.

Matched MeSH terms: Analgesics, Opioid/adverse effects*
Fulltext Influence of Cytochrome P450, Family 2, Subfamily D, Polypeptide 6 (CYP2D6) polymorphisms on pain sensitivity and clinical response to weak opioid analgesics

Zahari Z, Ismail R

Drug Metab. Pharmacokinet., 2014;29(1):29-43.
PMID: 23759977

CYP2D6 polymorphisms show large geographical and interethnic differences. Variations in CYP2D6 activity may impact upon a patient's pain level and may contribute to interindividual variations in the response to opioids. This paper reviews the evidence on how CYP2D6 polymorphisms might influence pain sensitivity and clinical response to codeine and tramadol. For example, it is shown that (1) CYP2D6 poor metabolizers (PMs) may be less efficient at synthesizing endogenous morphine compared with other metabolizers. In contrast, ultra-rapid metabolizers (UMs) may be more efficient than other metabolizers at synthesizing endogenous morphine, thus strengthening endogenous pain modulation. Additionally, for codeine and tramadol that are bioactivated by CYP2D6, PMs may undergo no metabolite formation, leading to inadequate analgesia. Conversely, UMs may experience quicker analgesic effects but be prone to higher mu-opioid-related toxicity. The literature suggested the potential usefulness of the determination of CYP2D6 polymorphisms in elucidating serious adverse events and in preventing subsequent inappropriate selection or doses of codeine and tramadol. Notably, even though many studies investigated a possible role of the CYP2D6 polymorphisms on pain sensitivity, pharmacokinetics and pharmacodynamics of these drugs, the results of analgesia and adverse effects are conflicting. More studies are required to demonstrate genetically determined unresponsiveness and risk of developing serious adverse events for patients with pain and these should involve larger numbers of patients in different population types.

Matched MeSH terms: Analgesics, Opioid/adverse effects
Long-Term Cognitive Effects of Kratom (Mitragyna speciosa Korth.) Use

Singh D, Narayanan S, Müller CP, Vicknasingam B, Yücel M, Ho ETW, et al.

J Psychoactive Drugs, 2018 12 15;51(1):19-27.
PMID: 30556488 DOI: 10.1080/02791072.2018.1555345

Kratom or Mitragyna speciosa (Korth.) is a medicinal plant of Southeast Asia. As a result of its opioid-like effects, it remains unknown whether consumption of kratom tea is associated with impaired cognitive function. We assessed the cognitive function of 70 regular kratom users and 25 control participants using the Cambridge Neuropsychological Test Automated Battery. Participants performed six neuropsychological tasks that assessed motor, learning and memory, attention and executive function. Relative to control participants, higher consumption (>3 glasses daily or mitragynine doses between 72.5 mg and 74.9 mg) of kratom tea was selectively associated with impaired performance on the Paired Associates Learning task, reflecting deficits in visual episodic memory and new learning. Overall, the performance of kratom users compared to control participants, and the performance of high (>3 glasses per day) as well as low (≤3 glasses per day) kratom using groups, were comparable on all neuropsychological domains. Higher intake of kratom juice (>3 glasses daily) did not appear to impair motor, memory, attention or executive function of regular kratom users.

Matched MeSH terms: Analgesics, Opioid/adverse effects
Fulltext Clinical factors associated with sexual dysfunction among men in methadone maintenance treatment and buprenorphine maintenance treatment: a meta-analysis study

Yee A, Loh HS, Hisham Hashim HM, Ng CG

Int J Impot Res, 2014 Sep-Oct;26(5):161-6.
PMID: 24990199 DOI: 10.1038/ijir.2014.18

Methadone maintenance treatment is proven to be effective treatment for opioid dependence. Of the many adverse events reported, sexual dysfunction is one of the most common side effects. However, there may be other clinical factors that are associated with sexual dysfunction among methadone users. We conducted a meta-analysis to examine the clinical factors associated with sexual dysfunction among male patients on methadone and buprenorphine treatments, of which eligible studies were selected using prior defined criteria. A total of 2619 participants from 16 eligible studies, published from inception till December 2012, were identified from the PubMed, OVID and EMBASE databases. The included studies provided prevalence estimates for sexual dysfunction among methadone users with a meta-analytical pooled prevalence of 52% (95% confidence interval (CI), 0.39-0.65). Only four studies compared sexual dysfunction between the two groups, with a significantly higher combined odds ratio in the methadone group (odds ratio=4.01, 95% CI, 1.52-10.55, P=0.0049). Our study shows that eight clinical factors are associated with sexual dysfunction among men receiving opioid substitution treatment, namely age, hormone assays, duration of treatment, methadone dose, medical status, psychiatric illness, other current substance use and familial status, and methadone versus buprenorphine treatment. Despite the methodological limitations, the findings of this meta-analysis study may offer better insights to clinicians in dealing with both sexual dysfunction and its related problems.

Matched MeSH terms: Analgesics, Opioid/adverse effects*
Fulltext Arthroscopy under local anaesthesia

Ramanathan R

Med J Malaysia, 1998 Sep;53 Suppl A:99-101.
PMID: 10968190

We studied 95 patients who underwent knee Arthroscopy under local anaesthesia between JANUARY 1995 till 1997. Materials used were 1% Xylocaine and 0.25% Bupivacaine of 20 mls each combined with midazolam 2 mg and IV pethidine 30 mgm for sedation. The patients were attached to monitors (pulse Oxymeter, ECG and BP and pulse recorders) and blood less field was created using a tornquet. The procedures lasted about 45 minutes. 90 out of 95 patients completed the procedures successfully without any complications. 2 developed respiratory embarrassments and were intubated and ventilated. 3 procedures abandoned and converted to general anaesthesia. The range of procedures done include meniscectomy, meniscal repair, synovial biopsy, debridement for osteoarthrosis, shaving of osteophytes, drilling of cartilage and bones and removal of loose bodies. This study is to show that knee arthroscopy under LA is a safe alternative in hospitals where GA time is limited.

Matched MeSH terms: Analgesics, Opioid/adverse effects
Fulltext The Future of Opioid Agonist Therapies in Ukraine: A Qualitative Assessment of Multilevel Barriers and Ways Forward to Promote Retention in Treatment

Bojko MJ, Mazhnaya A, Marcus R, Makarenko I, Islam Z, Filippovych S, et al.

J Subst Abuse Treat, 2016 07;66:37-47.
PMID: 27211995 DOI: 10.1016/j.jsat.2016.03.003

Opioid agonist therapies (OAT) to treat opioid addiction in people who inject drugs (PWID) began in Ukraine in 2004. Scale-up of OAT, however, has been hampered by both low enrollment and high attrition. To better understand the factors influencing OAT retention among PWID in Ukraine, qualitative data from 199 PWIDs were collected during 25 focus groups conducted in five Ukrainian cities from February to April 2013. The experiences of PWID who were currently or previously on OAT or currently trying to access OAT were analyzed to identify entry and retention barriers encountered. Transcribed data were analyzed using a grounded theory approach. Individual beliefs about OAT, particularly misaligned treatment goals between clients and providers, influenced PWID's treatment seeking behaviors. Multiple programmatic and structural issues, including inconvenient hours and treatment site locations, complicated dosing regimens, inflexible medication dispensing guidelines, and mistreatment by clinic and medical staff also strongly influenced OAT retention. Findings suggest the need for both programmatic and policy-level structural changes such as revising legal regulations covering OAT dispensing, formalizing prescription dosing policies and making OAT more available through other sites, including primary care settings as a way to improve treatment retention. Quality improvement interventions that target treatment settings could also be deployed to overcome healthcare delivery barriers. Additional patient education and medical professional development around establishing realistic treatment goals as well as community awareness campaigns that address the myths and fears associated with OAT can be leveraged to overcome individual, family and community-level barriers.

Matched MeSH terms: Analgesics, Opioid/adverse effects
The Use of Methylphenidate for Physical and Psychological Symptoms in Cancer Patients: A Review

Andrew BN, Guan NC, Jaafar NRN

Curr Drug Targets, 2018;19(8):877-887.
PMID: 28322161 DOI: 10.2174/1389450118666170317162603

BACKGROUND: One of the goals of cancer treatment is symptoms management especially at the end stage. The common symptoms in cancer include pain, fatigue, depression and cognitive dysfunction. The available treatment options for symptom management are limited. Methylphenidate, a psychostimulant, may be of benefit for these patients. In this report, we review the use of methylphenidate for symptoms control in cancer patients.
METHOD: Electronic literature search on PubMed was conducted using the following keywords: methylphenidate, cancer, carcinoma, oncology, oncological and tumour. We identified forty two relevant studies and publications on the use of methylphenidate in cancer patients to be included in this review.
RESULTS: Methylphenidate was found to have some evidence in reducing opioid-induced sedation, improving cognitive symptoms and reduction of fatigue in cancer patients. Nevertheless, the results were inconsistent due to variations in the study populations, study design and outcome measures, among others. There was minimal evidence on its use in treating depression. Otherwise, methylphenidate was generally well-tolerated by patients.
CONCLUSION: This review potentially supports the use of methylphenidate for opioid-induced sedation, cognitive decline and fatigue in cancer patients. Further placebo-controlled trials would help in strengthening the evidence for this treatment.

Matched MeSH terms: Analgesics, Opioid/adverse effects
Patterns and reasons for kratom (Mitragyna speciosa) use among current and former opioid poly-drug users

Singh D, Yeou Chear NJ, Narayanan S, Leon F, Sharma A, McCurdy CR, et al.

J Ethnopharmacol, 2020 Mar 01;249:112462.
PMID: 31816368 DOI: 10.1016/j.jep.2019.112462

ETHNOPHARMACOLOGICAL RELEVANCE: Kratom (Mitragyna speciosa) is a native medicinal plant of Southeast Asia widely reported to be used to reduce opioid dependence and mitigate withdrawal symptoms. There is also evidence to suggest that opioid poly-drug users were using kratom to abstain from opioids.
AIM OF THE STUDY: To determine the patterns and reasons for kratom use among current and former opioid poly-drug users in Malaysia.
MATERIALS AND METHODS: A total of 204 opioid poly-drug users (142 current users vs. 62 former users) with current kratom use history were enrolled into this cross-sectional study. A validated UPLC-MS/MS method was used to evaluate the alkaloid content of a kratom street sample.
RESULTS: Results from Chi-square analysis showed that there were no significant differences in demographic characteristics between current and former opioid poly-drug users except with respect to marital status. Current users had higher odds of being single (OR: 2.2: 95%CI: 1.21-4.11; p opioid poly-drug users (OR: 1.1: 0.62-2.06; p opioid users reported using kratom to ameliorate opioid withdrawal, current users had significantly higher likelihood of using kratom for that purpose (OR: 5.4: 95%CI: 2.81-10.18; p opioid users were more likely to be using kratom for its euphoric (mood elevating) effects (OR: 1.9: 95%CI: 1.04-3.50; p opioid poly-drug users regularly used kratom (three glasses or about 900 mL daily or the equivalent of 170.19 mg of mitragynine) to overcome opioid poly-drug use problems.

Matched MeSH terms: Analgesics, Opioid/adverse effects

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