Displaying publications 1 - 20 of 133 in total

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  1. Zin CS, Chen LC, Knaggs RD
    Eur J Pain, 2014 Oct;18(9):1343-51.
    PMID: 24756859 DOI: 10.1002/j.1532-2149.2014.496.x
    BACKGROUND: This study evaluated the prescribing trends of four commonly prescribed strong opioids in primary care and explored utilization in non-cancer and cancer users.
    METHODS: This cross-sectional study was conducted from 2000 to 2010 using the UK Clinical Practice Research Datalink. Prescriptions of buprenorphine, fentanyl, morphine and oxycodone issued to adult patients were included in this study. Opioid prescriptions issued after patients had cancer medical codes were defined as cancer-related use; otherwise, they were considered non-cancer use. Annual number of prescriptions and patients, defined daily dose (DDD/1000 inhabitants/day) and oral morphine equivalent (OMEQ) dose were measured in repeat cross-sectional estimates.
    RESULTS: In total, there were 2,672,022 prescriptions (87.8% for non-cancer) of strong opioids for 178,692 users (59.9% female, 83.9% non-cancer, mean age 67.1 ± 17.0 years) during the study period. The mean annual (DDD/1000 inhabitants/day) was higher in the non-cancer group than in the cancer group for all four opioids; morphine (0.73 ± 0.28 vs. 0.12 ± 0.04), fentanyl (0.46 ± 0.29 vs. 0.06 ± 0.24), oxycodone (0.24 ± 0.19 vs. 0.038 ± 0.028) and buprenorphine (0.23 ± 0.15 vs. 0.008 ± 0.006). The highest proportion of patients were prescribed low opioid doses (OMEQ ≤ 50 mg/day) in both non-cancer (50.3%) and cancer (39.9%) groups, followed by the dose ranks of 51-100 mg/day (26.2% vs. 28.7%), 101-200 mg/day (15.1% vs. 19.2%) and >200 mg/day (8.25% vs. 12.1%).
    CONCLUSIONS: There has been a huge increase in strong opioid prescribing in the United Kingdom, with the majority of prescriptions for non-cancer pain. Morphine was the most frequently prescribed, but the utilization of oxycodone, buprenorphine and fentanyl increased markedly over time.
    Matched MeSH terms: Analgesics, Opioid/administration & dosage; Analgesics, Opioid/therapeutic use*
  2. Zin CS
    J Pharm Bioallied Sci, 2020 Nov;12(Suppl 2):S841-S845.
    PMID: 33828387 DOI: 10.4103/jpbs.JPBS_251_19
    Background: Analgesic is commonly used in children but little is known about its patterns of utilization. This study explored the patterns of analgesic prescribing in children.

    Materials and Methods: This cross-sectional study used prescription databases of tertiary hospital settings in Malaysia from 2010 to 2016. Prescriptions for nine NSAIDs (diclofenac, ketoprofen, etoricoxib, celecoxib, ibuprofen, indomethacin, mefenamic acid, meloxicam, and naproxen), tramadol, and five other opioids (morphine, oxycodone, fentanyl, buprenorphine, and dihydrocodeine) prescribed for children aged <18 years were included. Number of annual patients and prescriptions were measured and analyzed using Stata v15.

    Results: During a 7-year study period, a total of 5040 analgesic prescriptions of the nine NSAIDs, tramadol, and five other opioids were prescribed for 2460 pediatric patients (81.8% NSAIDs patients, 17.9% tramadol patients, and 0.3% opioid patients). Ibuprofen was the primary analgesic in young children less than 12 years old (≤2 years old [y.o.] [75%], 3-5 y.o. [85%], and 6-12 y.o. [56.3%]). However, there was a wide range of analgesics used in older children (>12 y.o.) with the majority for naproxen (13-15 y.o. (28.2%) and 16-17 y.o. (28.2%). Other frequently prescribed analgesics for older children included ibuprofen (20.6%) and diclofenac (18.2%) for 12-15 y.o. and diclofenac (26.7%) and tramadol (17.6%) for 16-17 y.o.

    Conclusion: Ibuprofen was the primary analgesic for children less than 12 y.o., whereas there was a wide range of analgesics prescribed for children age >12 y.o. including naproxen, diclofenac, and tramadol.

    Matched MeSH terms: Analgesics, Opioid
  3. Zin CS
    J Pharm Bioallied Sci, 2020 Nov;12(Suppl 2):S846-S851.
    PMID: 33828388 DOI: 10.4103/jpbs.JPBS_252_19
    Background: It was reported that opioid consumption in developing countries was stagnated or decreased, but precise data on the consumption are unclear. This study examined the trends and patterns of opioid consumption in Malaysia and other four Southeast Asian countries.

    Materials and Methods: Data of five strong opioids consumption (morphine, oxycodone, fentanyl, pethidine, and methadone) between 2005 and 2014 from Malaysia, Singapore, Indonesia, Thailand, and Vietnam were extracted from the Pain and Policy Studies Group. Defined daily doses per 1000 inhabitants per day (DDD/1000 inhabitants/day) was used for calculating the annual amount of opioid use.

    Results: The total consumption of five strong opioids was increased in all five Southeast Asian countries during a 10-year study period. Malaysia was recorded with the largest increase of the opioid consumption (993.18%), followed by Indonesia (530.34%), Vietnam (170.17%), Singapore (116.16%), and Thailand (104.66%). Malaysia also had the highest total strong opioid consumption (11.2 DDD/1000 inhabitants/day), primarily for methadone. Among the opioids used for pain management, fentanyl was primarily used in Malaysia and Singapore but the greatest increase in these two countries was for oxycodone. Fentanyl was also primarily used in Indonesia while morphine was predominantly used in Thailand and Vietnam.

    Conclusion: Growing trends of strong opioids consumption in all five Southeast Asian countries demonstrated in this study may indicate improved access to opioid analgesics in these countries. Given the increasing trends, it is important to ensure that the utilization of opioids is according to the guideline to prevent the negative consequences of opioids particularly when used in chronic non-cancer pain.

    Matched MeSH terms: Analgesics, Opioid
  4. Zin CS, Rahman NA, Ismail CR, Choy LW
    Pain Pract, 2017 07;17(6):774-781.
    PMID: 27676695 DOI: 10.1111/papr.12525
    BACKGROUND: There are currently limited data available on the patterns of opioid prescribing in Malaysia. This study investigated the patterns of opioid prescribing and characterized the dosing and duration of opioid use in patients with noncancer and cancer pain.
    METHODS: This retrospective, cross-sectional study was conducted at an outpatient hospital setting in Malaysia. All prescriptions for opioids (dihydrocodeine, fentanyl, morphine, and oxycodone) issued between January 2013 and December 2014 were examined. The number of prescriptions and patients, the distribution of mean daily dose, annual total days covered with opioids, and annual total opioid dose at the individual level were calculated and stratified by noncancer and cancer groups.
    RESULTS: A total of 1015 opioid prescriptions were prescribed for 347 patients from 2013 to 2014. Approximately 41.5% of patients (N = 144/347) and 58.5% (N = 203/347) were associated with noncancer and cancer diagnosis, respectively. Oxycodone (38.0%) was the highest prescribed primarily for the noncancer group. The majority of patients in both noncancer (74.3%) and cancer (60.4%) groups were receiving mean daily doses of < 50 mg morphine equivalents. The chronic use of opioids (> 90 days per year) was associated with 21.8% of patients in the noncancer group and 17.5% in the cancer group.
    CONCLUSIONS: The finding from this study showed that 41.5% of opioid users at an outpatient hospital setting in Malaysia received opioids for noncancer pain and 21.8% of these users were using opioids for longer than 90 days. The average daily dose in the majority of patients in both groups of noncancer and cancer was modest.
    Study site: outpatient clinic, hospital, Malaysia
    Matched MeSH terms: Analgesics, Opioid/administration & dosage*
  5. Zin CS, Nazar NI, Rahman NS, Alias NE, Ahmad WR, Rani NS, et al.
    J Pain Res, 2018;11:1959-1966.
    PMID: 30288090 DOI: 10.2147/JPR.S164774
    Purpose: To examine the trends of analgesic prescribing at public tertiary hospital outpatient settings and explore the patterns of their utilization in nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol, and opioid patients.
    Patients and methods: This cross-sectional study was conducted from 2010 to 2016 using the prescription databases of two tertiary hospitals in Malaysia. Prescriptions for nine NSAIDs (ketoprofen, diclofenac, celecoxib, etoricoxib, ibuprofen, indomethacin, meloxicam, mefenamic acid, and naproxen), tramadol, and five other opioids (morphine, fentanyl, oxycodone, dihydrocodeine, and buprenorphine) were included in this study. Annual number of patients and prescriptions were measured in repeat cross-sectional estimates. Descriptive statistics and linear trend analysis were performed using Stata version 13.
    Results: A total of 192,747 analgesic prescriptions of the nine NSAIDs, tramadol, and five other opioids were given for 97,227 patients (51.8% NSAIDs patients, 46.6% tramadol patients, and 1.7% opioid patients) from 2010 to 2016. Tramadol (37.9%, n=72,999) was the most frequently prescribed analgesic, followed by ketoprofen (17.5%, n=33,793), diclofenac (16.2%, n=31,180), celecoxib (12.2%, n=23,487), and other NSAIDs (<4.5%). All the analgesics were increased over time except meloxicam, indomethacin, and mefenamic acid. Opioids, primarily morphine (2.2%, n=4,021) and oxycodone (0.5%, n=1,049), were prescribed the least, but the rate of increase was the highest.
    Conclusion: Tramadol was the most frequently prescribed analgesic in hospital outpatient settings in Malaysia. Opioids were prescribed the least, but noted the highest increase in utilization.
    Data source: Prescription databases of two public tertiary hospitals in Malaysia

    Study site: two public tertiary hospitals in Malaysia
    Matched MeSH terms: Analgesics, Opioid
  6. Zin CS, Taufek NH, Ahmad MM
    Front Pharmacol, 2019;10:1286.
    PMID: 31736760 DOI: 10.3389/fphar.2019.01286
    Limited data are available on the adherence to opioid therapy and the influence of different patient groups on adherence. This study examined the patterns of adherence in opioid naïve and opioid existing patients with varying age and gender. This retrospective cohort study was conducted using the prescription databases in tertiary hospital settings in Malaysia from 2010 to 2016. Adult patients aged ≥18 years, receiving at least two opioid prescriptions, were included and stratified into the opioid naïve and existing patient groups. Adherence to opioid therapy was measured using the proportion of days covered (PDC), which was derived by dividing the total number of days covered with any opioids by the number of days in the follow-up period. Generalized linear modeling was used to assess factors associated with PDC. A total of 10,569 patients with 36,650 prescription episodes were included in the study. Of these, 91.7% (n = 9,696) were opioid naïve patients and 8.3% (n = 873) were opioid existing patients. The median PDC was 35.5% (interquartile range (IQR) 10.3-78.7%) and 26.8% (IQR 8.8-69.5%) for opioid naïve and opioid existing patients, respectively. A higher opioid daily dose (coefficient 0.010, confidence interval (CI) 0.009, 0.012 p < 0.0001) and increasing age (coefficient 0.002, CI 0.001, 0.003 p < 0.0001) were associated with higher levels of PDC, while lower PDC values were associated with male subjects (coefficient -0.0041, CI -0.072, -0.010 p = 0.009) and existing opioid patients (coefficient -0.134, CI -0.191, -0.077 p < 0.0001). The suboptimal adherence to opioid medications was commonly observed among patients with non-cancer pain, and the opioid existing patients were less adherent compared to opioid naïve patients. Increasing age and a higher daily opioid dose were factors associated with higher levels of adherence, while male and opioid existing patients were potential determinants for lower levels of adherence to opioid medications.
    Matched MeSH terms: Analgesics, Opioid
  7. Zin CS, Nazar NI, Rahman NSA, Ahmad WR, Rani NS, Ng KS
    BMJ Open, 2019 07 02;9(7):e027203.
    PMID: 31270113 DOI: 10.1136/bmjopen-2018-027203
    OBJECTIVE: This study examined opioid prescription initiation patterns and their association with short-term and long-term opioid use among opioid-naïve patients.

    DESIGN: This study was designed as a retrospective cohort study.

    SETTING AND PARTICIPANTS: In this study, we analysed the prescription databases of tertiary hospitals in Malaysia. This study included patients aged ≥18 years with at least one opioid prescription (buprenorphine, morphine, oxycodone, fentanyl, dihydrocodeine or tramadol) between 1 January 2011 and 31 December 2016. These patients had no opioid prescriptions in the 365 days prior, and were followed up for 365 days after the initial opioid prescription.

    MAIN OUTCOME MEASURES: The main outcome measures were the number of short-term (<90 days) and long-term opioid users (≥90 days), initial opioid prescription period and daily dose.

    RESULTS: There were 33 752 opioid-naïve patients who received opioid prescriptions (n=43 432 prescriptions) during the study period. Of these, 29 824 (88.36%) were short-term opioid users and 3928 (11.64%) were long-term opioid users. The majority of these short-term (99.09%) and long-term users (96.18%) received an initial daily opioid dose of <50 mg/day with a short-acting opioid formulation. Short-term opioid users were predominantly prescribed opioids for 3-7 days (59.06%) by the emergency department (ED, 60.56%), while long-term opioid users were primarily prescribed opioids for ≥7 days (91.85%) by non-ED hospital departments (91.8%). The adjusted model showed that the following were associated with long-term opioid use: increasing opioid daily doses, prescription period ≥7 days and long-acting opioids initiated by non-EDs.

    CONCLUSIONS: The majority of opioid-naïve patients in tertiary hospital settings in Malaysia were prescribed opioids for short-term use. The progression to long-term use among opioid-naïve patients was attributed to the prescription of higher opioid doses for a longer duration as well as long-acting opioids initiated by non-ED hospital departments.

    Matched MeSH terms: Analgesics, Opioid/pharmacology*
  8. Zelenev A, Michael L, Li J, Altice FL
    Int J Drug Policy, 2024 Jan;123:104250.
    PMID: 38088004 DOI: 10.1016/j.drugpo.2023.104250
    BACKGROUND: Opioid agonist therapies (OAT) and  harm reduction such as syringe service programs (SSP) have been shown to be effective in preventing adverse outcomes such as overdose deaths, HIV and Hepatitis C infections among people who inject drugs (PWID). The importance of social network influence on disease transmission is well established, yet the interplay between harm reduction and network structures is, generally, not well understood. This study aims to analyze how social networks can mediate the harm reduction effects associated with secondary exchange through syringe service programs (SSP) and opioid agonist therapies (OAT) among injection network members.

    METHODS: Sociometric data on networks on people who inject drugs from Hartford, CT, which were collected in 2012-2013, provided assessment of risk behaviors among 1574 injection network members, including participation in OAT and SSP. Subject's network characteristics were examined in relation to retention in OAT, as well as secondary syringe exchange using exponential random graph model (ERGM) and regression.

    RESULTS: Based on the analysis, we found that probability of individuals being retained in OAT was positively associated with the OAT retention status of their peers within the network. Using simulations, we found that higher levels of positive correlation of OAT retention among network members can result in reduced risk of transmission of HIV to network partners on OAT. In addition, we found that secondary syringe exchange engagement was associated with higher probability of sharing of paraphernalia and unsterile needles at the network level.

    CONCLUSIONS: Understanding how networks mediate risk behaviors is crucial for making progress toward ending the HIV epidemic.

    Matched MeSH terms: Analgesics, Opioid/therapeutic use
  9. Zakaria ZA, Mohd Sani MH, Cheema MS, Kader AA, Kek TL, Salleh MZ
    PMID: 24555641 DOI: 10.1186/1472-6882-14-63
    Muntingia calabura (Elaecoparceae) is a medicinal plant traditionally used, particularly, by the Peruvian people to alleviate headache and cold, pain associated with gastric ulcers or to reduce the prostate gland swelling. Following the recent establishment of antinociceptive activity of M. calabura leaf, the present study was performed to further elucidate on the possible mechanisms of antinociception involved.
    Matched MeSH terms: Analgesics, Opioid/analysis; Analgesics, Opioid/pharmacology; Analgesics, Opioid/therapeutic use
  10. Zakaria ZA, Kumar GH, Mat Jais AM, Sulaiman MR, Somchit MN
    Methods Find Exp Clin Pharmacol, 2008 Jun;30(5):355-62.
    PMID: 18806894 DOI: 10.1358/mf.2008.30.5.1186084
    The present study was carried out to elucidate the antinociceptive, antiinflammatory and antipyretic properties of the aqueous and lipid-based extracts of Channa striatus fillet in rats. The antinociceptive activity was assessed using the formalin test, and the antiinflammatory and antipyretic activities were assessed using the carrageenan-induced paw edema and brewer's yeast-induced pyrexia tests, respectively. Both types of extracts were prepared in concentrations of 10%, 50% and 100% by serial dilution in distilled water or dimethyl sulfoxide, respectively, and were administered subcutaneously 30 min prior to each test. Except for the 10% aqueous extract which exhibits activity only in the early phase, the extracts were found to exhibit significant (P < 0.05) activity in the early and late phases of the formalin test. Furthermore, the aqueous and lipid-based extracts were also found to show significant (P < 0.05) antiinflammatory activity, with the former showing a greater effect at the lowest concentration used. The lipidbased, but not the aqueous, extract was found to have significant (P < 0.05) activity in the pyrexia test. In conclusion, the present study demonstrated that C. striatus extracts possess antinociceptive, antiinflammatory and antipyretic activities.
    Matched MeSH terms: Analgesics, Opioid/pharmacology
  11. Zakaria ZA, Safarul M, Valsala R, Sulaiman MR, Fatimah CA, Somchit MN, et al.
    Naunyn Schmiedebergs Arch Pharmacol, 2005 Jul;372(1):55-62.
    PMID: 16133487
    A series of preliminary studies was carried out to evaluate the antinociceptive (pain relief) activity of the aqueous extract of Corchorus olitorius L. leaves (COAE) and to determine the influence of temperature and opioid receptors on COAE activity using the abdominal constriction and hot plate tests in mice. COAE, at concentrations of 10, 25, 50, 75, and 100%, showed both peripheral and central antinociception that are non-concentration- and concentration-dependent respectively. The peripheral activity was clearly observed at a concentration of 25% and diminished at a concentration of 100%, while the central activity was observed at all the concentrations of COAE used. Furthermore, the insignificant results obtained indicated that this peripheral activity (at concentrations of 25 and 50%) was comparable to that of morphine (0.8 mg/kg). Pre-heating COAE at a temperature of 80 degrees C and 100 degrees C, or 60 degrees C and 80 degrees C was found to enhance its peripheral and central antinociception respectively. Pre-treatment with naloxone (10 mg/kg), a general opioid receptor antagonist, for 5 min, followed by COAE, was found to completely block its peripheral, but not central, antinociceptive activity. Based on this observation, we conclude that the antinociceptive activity exhibited by C. olitorius is enhanced by the increase in temperature and may be mediated peripherally, but not centrally, at least in part, via an opioid receptor.
    Matched MeSH terms: Analgesics, Opioid/administration & dosage
  12. Zakaria ZA, Roosli RAJ, Marmaya NH, Omar MH, Basir R, Somchit MN
    Biomolecules, 2020 02 12;10(2).
    PMID: 32059475 DOI: 10.3390/biom10020280
    Dicranopteris linearis leaf has been reported to exert antinociceptive activity. The present study elucidates the possible mechanisms of antinociception modulated by the methanol extract of D. linearis leaves (MEDL) using various mouse models. The extract (25, 150, and 300 mg/kg) was administered orally to mice for 30 min priot to subjection to the acetic acid-induced writhing-, hot plate- or formalin-test to establish the antinociceptive profile of MEDL. The most effective dose was then used in the elucidation of possible mechanisms of action stage. The extract was also subjected to the phytochemical analyses. The results confirmed that MEDL exerted significant (p < 0.05) antinociceptive activity in those pain models as well as the capsaicin-, glutamate-, bradykinin- and phorbol 12-myristate 13-acetate (PMA)-induced paw licking model. Pretreatment with naloxone (a non-selective opioid antagonist) significantly (p < 0.05) reversed MEDL effect on thermal nociception. Only l-arginine (a nitric oxide (NO) donor) but not N(ω)-nitro-l-arginine methyl ester (l-NAME; a NO inhibitor) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; a specific soluble guanylyl cyclase inhibitor) significantly (p < 0.05) modified MEDL effect on the writhing test. Several polyphenolics and volatile antinociceptive compounds were detected in MEDL. In conclusion, MEDL exerted the opioid/NO-mediated antinociceptive activity, thus, justify D. linearis as a potential source for new analgesic agents development.
    Matched MeSH terms: Analgesics, Opioid/metabolism*
  13. Zakaria ZA, Sani MH, Mohammat MF, Mansor NS, Shaameri Z, Kek TL, et al.
    Can J Physiol Pharmacol, 2013 Dec;91(12):1143-53.
    PMID: 24289087 DOI: 10.1139/cjpp-2013-0099
    This study was carried out to determine the antinociceptive activity of a novel synthetic oxopyrrolidine-based compound, (2R,3R,4S)-ethyl 4-hydroxy-1,2-dimethyl-5-oxopyrrolidine-3-carboxylate (ASH21374), and to elucidate the involvement of the opioid, vanilloid, glutamate, and nitric oxide - cyclic guanosine monophosphate (NO/cGMP) systems in modulating the observed antinociception. ASH21374, in the doses of 2, 10, and 100 mg/kg body mass, was administered orally to mice 60 mins prior to exposure to various antinociceptive assays. From the results obtained, ASH21374 exhibited significant (P < 0.05) antinociceptive activity in the abdominal constriction, hot-plate, and formalin tests that was comparable with 100 mg/kg acetylsalicylic acid or 5 mg/kg morphine, respectively. ASH21374 also attenuated capsaicin- and glutamate-induced paw licking. Pre-treatment with 5 mg/kg naloxone significantly (P < 0.05) inhibited the activity in all assays, while pretreatment with 10 mg/kg β-funaltraxamine, 1 mg/kg naltrindole, or 1 mg/kg nor-binaltorphimine significantly (P < 0.05) reversed the activity in the abdominal constriction test. l-Arginine, N(G)-nitro-l-arginine methyl esters (l-NAME), methylene blue, and their combinations, failed to inhibit the ASH21374 antinociceptive activity. In conclusion, ASH21374 demonstrated antinociceptive activities on the peripheral and central nervous systems, mediated through the activation of opioid receptors, inhibition of the glutamatergic system, and attenuation of vanilloid-mediated nociceptive transmission. Further studies have been planned to determine the pharmacological potential of ASH21374.
    Matched MeSH terms: Analgesics, Opioid/metabolism
  14. Zakaria ZA, Abdul Rahim MH, Roosli RAJ, Mohd Sani MH, Omar MH, Mohd Tohid SF, et al.
    Pain Res Manag, 2018;2018:9536406.
    PMID: 29686743 DOI: 10.1155/2018/9536406
    Methanolic extract of Clinacanthus nutans Lindau leaves (MECN) has been proven to possess antinociceptive activity that works via the opioid and NO-dependent/cGMP-independent pathways. In the present study, we aimed to further determine the possible mechanisms of antinociception of MECN using various nociceptive assays. The antinociceptive activity of MECN was (i) tested against capsaicin-, glutamate-, phorbol 12-myristate 13-acetate-, bradykinin-induced nociception model; (ii) prechallenged against selective antagonist of opioid receptor subtypes (β-funaltrexamine, naltrindole, and nor-binaltorphimine); (iii) prechallenged against antagonist of nonopioid systems, namely, α2-noradrenergic (yohimbine), β-adrenergic (pindolol), adenosinergic (caffeine), dopaminergic (haloperidol), and cholinergic (atropine) receptors; (iv) prechallenged with inhibitors of various potassium channels (glibenclamide, apamin, charybdotoxin, and tetraethylammonium chloride). The results demonstrated that the orally administered MECN (100, 250, and 500 mg/kg) significantly (p < 0.05) reversed the nociceptive effect of all models in a dose-dependent manner. Moreover, the antinociceptive activity of 500 mg/kg MECN was significantly (p < 0.05) inhibited by (i) antagonists of μ-, δ-, and κ-opioid receptors; (ii) antagonists of α2-noradrenergic, β-adrenergic, adenosinergic, dopaminergic, and cholinergic receptors; and (iii) blockers of different K+ channels (voltage-activated-, Ca2+-activated, and ATP-sensitive-K+ channels, resp.). In conclusion, MECN-induced antinociception involves modulation of protein kinase C-, bradykinin-, TRVP1 receptors-, and glutamatergic-signaling pathways; opioidergic, α2-noradrenergic, β-adrenergic, adenosinergic, dopaminergic, and cholinergic receptors; and nonopioidergic receptors as well as the opening of various K+ channels. The antinociceptive activity could be associated with the presence of several flavonoid-based bioactive compounds and their synergistic action with nonvolatile bioactive compounds.
    Matched MeSH terms: Analgesics, Opioid/metabolism
  15. 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; Analgesics, Opioid/pharmacokinetics; Analgesics, Opioid/therapeutic use*
  16. Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al.
    J Pharm Pharm Sci, 2016;19(1):127-36.
    PMID: 27096697 DOI: 10.18433/J3NS49
    PURPOSE: This study compared pain sensitivity among opioid dependent patients on methadone maintenance therapy (MMT) and opioid naive subjects.

    METHODS: The three hundred participants comprised 152 opioid naive subjects and 148 opioid dependent patients. Opioid naive subjects had not taken any opioids including morphine and methadone to their best knowledge and were presumed so after two consecutive negative urine screenings for drugs. All opioid dependent patients were stabilized in treatment, defined as having been enrolled in the program for more than one month with no change of methadone dosage over the past one month. Excluded from the study were individuals with chronic or ongoing acute pain and individuals with a history of analgesics ingestion within 3 d before the cold pressor test (CPT). Pain tolerance to CPT was evaluated at 0 h, and at 2, 4, 8, 12, and 24 h post-methadone dose.

    RESULTS: Patients exhibited a significantly shorter mean pain tolerance time of 34.17 s (95% CI 24.86, 43.49) versus 61.36 (52.23, 70.48) [p < 0.001] compared with opioid naive subjects. Time-dependent mean pain tolerance was also significantly different when naive subjects were compared to patients (p = 0.016).

    CONCLUSIONS: This study revealed hyperalgesia amongst patients on MMT, as manifested by their quicker hand withdrawal. The complaints of pain in this population should not be underestimated and the pain should be evaluated seriously and managed aggressively.

    Matched MeSH terms: Analgesics, Opioid/administration & dosage*
  17. Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al.
    Drug Alcohol Depend, 2016 08 01;165:143-50.
    PMID: 27289271 DOI: 10.1016/j.drugalcdep.2016.05.028
    BACKGROUND: CYP2B6 polymorphisms contribute to inter-individual variations in pharmacokinetics of methadone. Increased pain sensitivity is frequently reported by opioid dependent patients on methadone maintenance therapy (MMT). It is possible, therefore, that genetic polymorphisms in CYP2B6, which affects the metabolism of methadone, influence pain sensitivity among patients on MMT. This study investigated CYP2B6 polymorphisms and pain sensitivity in this group.

    METHODS: The cold pressor pain responses of 148 opioid dependent patients receiving MMT were evaluated using the cold pressor test (CPT). DNA was extracted from whole blood and subjected to polymerase chain reaction (PCR)-genotyping.

    RESULTS: Of the 148 subjects, 77 (52.0%) were carriers of CYP2B6*6 allele. CYP2B6*6 allele carriers had shorter cold pain threshold and pain tolerance times than non-carriers of CYP2B6*6 allele (21.05s vs 33.69s, p=0.036 and 27.15s vs 44.51s, p=0.020, respectively). Pain intensity scores of the CYP2B6*6 allele carriers was 67.55, whereas that of the CYP2B6*6 allele non-carriers was 64.86 (p=0.352).

    CONCLUSION: Our study indicates that the CYP2B6*6 allele is associated with a lower pain threshold and lower pain tolerance among males with opioid dependence on MMT. The CYP2B6*6 allele may provide a mechanistic explanation for clinical observations of heightened pain sensitivity among opioid dependent patients receiving MMT.

    Matched MeSH terms: Analgesics, Opioid/therapeutic use
  18. Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al.
    J Pharm Bioallied Sci, 2020 Nov;12(Suppl 2):S787-S803.
    PMID: 33828379 DOI: 10.4103/jpbs.JPBS_248_19
    Introduction: Dopamine receptor D2 (DRD2) is one of the dopamine receptors that have been studied in relation to opioid dependence. It is possible, therefore, that DRD2 gene (DRD2) polymorphisms influence treatment outcomes of patients with opioid dependence. The objective of this study was to investigate the influence of DRD2 polymorphisms on the clinical outcomes of opioid-dependent patients on methadone maintenance therapy (MMT).

    Materials and Methods: Patients with opioid dependence (n = 148) were recruited from MMT clinics. Pain sensitivity, severity of the opiate withdrawal syndrome, and sleep quality were assessed using cold pressor test (CPT), Subjective Opiate Withdrawal Scale (SOWS-M), and Pittsburgh Sleep Quality Index (PSQI)-Malay, respectively. Deoxyribonucleic acid (DNA) was extracted from whole blood, and then was used for genotyping of Val96Ala, Leu141Leu, Val154Ile, Pro310Ser, Ser311Cys, TaqI A, -141C Ins/Del, and A-241G polymorphisms.

    Results: Among 148 patients, 8.1% (n = 12), 60.8% (n = 90), 27.7% (n = 41), and 29.1% (n = 43) had at least one risk allele for Ser311Cys, TaqI A, -141C Ins/Del, and A-241G polymorphisms, respectively. There were no significant differences in pain responses (pain threshold, tolerance, and intensity), SOWS, and PSQI scores between DRD2 polymorphisms.

    Conclusion: The common DRD2 polymorphisms are not associated with pain sensitivity, severity of the opiate withdrawal syndrome, and sleep quality in patients with opioid dependence on MMT. However, this may be unique for Malays. Additional research should focus on investigating these findings in larger samples and different ethnicity.

    Matched MeSH terms: Analgesics, Opioid
  19. Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al.
    Pain Pract, 2017 09;17(7):930-940.
    PMID: 27996183 DOI: 10.1111/papr.12546
    BACKGROUND: Endogenous and exogenous opioids are substrates of the permeability glycoprotein (P-gp) efflux transporter, which is encoded by the ABCB1 (MDR1) gene. Genetic polymorphisms of ABCB1 may contribute to interindividual differences in pain modulation and analgesic responses. We investigated the relationship between ABCB1 polymorphisms and cold pain sensitivity among healthy males.

    METHODS: Cold pain responses, including pain threshold and pain tolerance, were measured using the cold-pressor test (CPT). DNA was extracted from whole blood and genotyped for ABCB1 polymorphisms, including c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642), using the allelic discrimination real-time polymerase chain reaction.

    RESULTS: A total of 152 participants were recruited in this observational study. Frequencies of mutated allele for c.1236C>T, c.2677G>T/A, and c.3435C>T polymorphisms were 56.6%, 49.7%, and 43.4%, respectively. Our results revealed an association of the CGC/CGC diplotype (c.1236C>T, c.2677G>T/A, and c.3435C>T) with cold pain sensitivity. Participants with the CGC/CGC diplotype had 90% and 72% higher cold pain thresholds (87.62 seconds vs. 46.19 seconds, P = 0.010) and cold pain tolerances (97.24 seconds vs. 56.54 seconds, P = 0.021), respectively, when compared with those without the diplotype.

    CONCLUSION: The CGC/CGC diplotype of ABCB1 polymorphisms was associated with variability in cold pain threshold and pain tolerance in healthy males.

    Matched MeSH terms: Analgesics, Opioid*
  20. Zahari Z, Inrahim MA, Tan SC, Mohamad N, Ismail R
    Turk J Med Sci, 2016 Dec 20;46(6):1743-1748.
    PMID: 28081321 DOI: 10.3906/sag-1507-132
    BACKGROUND/AIM: Sleep disturbances may contribute to poor treatment outcomes in opioid-dependent patients. The extent to which the sleep profiles of opioid-dependent patients differ from those of the general Malaysian population is not documented. This study compared opioid-naive subjects and opioid-dependent patients on methadone maintenance therapy (MMT) in terms of their sleep quality.

    MATERIALS AND METHODS: Participants comprised Malay male opioid-naive subjects (n = 159) and opioid-dependent patients (n = 160) from MMT clinics in Kelantan, Malaysia, between March and October 2013. Sleep quality was evaluated using the translated and validated Malay version of the Pittsburgh Sleep Quality Index (PSQI).

    RESULTS: The opioid-dependent patients exhibited higher global PSQI scores [adjusted mean (95% CI) = 5.46 (5.02, 5.90)] than the opioid-naive group [4.71 (4.26, 5.15)] [F (1, 313) = 4.77, P = 0.030].

    CONCLUSION: This study confirmed the poorer sleep quality among opioid-dependent patients on MMT, as manifested by their higher global PSQI scores. The sleep complaints in this patient population are a factor to consider and, when necessary, sleep evaluation and treatment should be undertaken to improve MMT patients' quality of sleep and overall treatment outcome.

    Matched MeSH terms: Analgesics, Opioid
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