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Method development and validation of a high-performance liquid chromatographic method for tramadol in human plasma using liquid-liquid extraction

Gan SH, Ismail R, Wan Adnan WA, Wan Z

J Chromatogr B Analyt Technol Biomed Life Sci, 2002 May 25;772(1):123-9.
PMID: 12016023

An HPLC system using a simple liquid-liquid extraction and HPLC with UV detection has been validated to determine tramadol concentration in human plasma. The method developed was selective and linear for concentrations ranging from 10 to 2000 ng/ml with average recovery of 98.63%. The limit of quantitation (LOQ) was 10 ng/ml and the percentage recovery of the internal standard phenacetin was 76.51%. The intra-day accuracy ranged from 87.55 to 105.99% and the inter-day accuracy, 93.44 to 98.43% for tramadol. Good precision (5.32 and 6.67% for intra- and inter-day, respectively) was obtained at LOQ. The method has been applied to determine tramadol concentrations in human plasma samples for a pharmacokinetic study.

Matched MeSH terms: Tramadol/administration & dosage; Tramadol/blood*; Tramadol/pharmacokinetics
Validation of a high-performance liquid chromatography method for tramadol and o-desmethyltramadol in human plasma using solid-phase extraction

Gan SH, Ismail R

J Chromatogr B Biomed Sci Appl, 2001 Aug 15;759(2):325-35.
PMID: 11499486

An HPLC system using solid-phase extraction and HPLC with UV detection has been validated in order to determine tramadol and o-desmethyltramadol (M1) concentrations in human plasma. The method developed was selective and linear for concentrations ranging from 50 to 3,500 ng/ml (tramadol) and 50 to 500 ng/ml (M1) with mean recoveries of 94.36 +/- 12.53% and 93.52 +/- 7.88%, respectively. Limit of quantitation (LOQ) was 50 ng/ml. For tramadol, the intra-day accuracy ranged from 95.48 to 114.64% and the inter-day accuracy, 97.21 to 103.24%. Good precision (0.51 and 18.32% for intra- and inter-day, respectively) was obtained at LOQ. The system has been applied to determine tramadol concentrations in human plasma samples for a pharmacokinetic study.

Matched MeSH terms: Tramadol/analogs & derivatives*; Tramadol/blood*; Tramadol/pharmacokinetics; Tramadol/therapeutic use
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: Tramadol/adverse effects; Tramadol/pharmacokinetics; Tramadol/therapeutic use
Impact of CYP2D6 genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics

Gan SH, Ismail R, Wan Adnan WA, Zulmi W

Mol Diagn Ther, 2007;11(3):171-81.
PMID: 17570739

Tramadol is metabolized by the highly polymorphic enzyme cytochrome P450 (CYP)2D6. Patients with different CYP2D6 genotypes may respond differently to tramadol in terms of pain relief and adverse events. In this study, we compare the pharmacokinetics and effects of tramadol in Malaysian patients with different genotypes to establish the pharmacokinetic-pharmacodynamic relationship of tramadol.

Matched MeSH terms: Tramadol/pharmacokinetics; Tramadol/pharmacology*
Population pharmacokinetic modelling of tramadol with application of the NPEM algorithms

Gan SH, Ismail R, Wan Adnan WA, Zulmi W, Jelliffe RW

J Clin Pharm Ther, 2004 Oct;29(5):455-63.
PMID: 15482390

Although the kinetic behaviour of tramadol has been described, the present study is the first to our knowledge, to report specifically on the population pharmacokinetic modelling of tramadol hydrochloride.

Matched MeSH terms: Tramadol/administration & dosage; Tramadol/pharmacokinetics*
Epidural tramadol for postoperative pain relief

Delilkan AE, Vijayan R

Anaesthesia, 1993 Apr;48(4):328-31.
PMID: 8494137

The efficacy of epidurally administered tramadol hydrochloride, a weak centrally acting analgesic, was studied for the relief of postoperative pain. Sixty patients undergoing abdominal surgery were randomly allocated to three treatment groups to be given the following agents by the epidural route: group 1 tramadol 50 mg; group 2 tramadol 100 mg; group 3 10 ml of bupivacaine 0.25%. The drugs were administered at the patients' request with each patient being allowed four doses in the first 24 h following surgery. Blood pressure, pulse rate, respiratory rate, arterial blood gas analyses, pain scores, the interval between doses and the occurrence of any side effects were recorded. Pain scores (assessed using a visual analogue scale) were significantly less (p < 0.05) at 3, 12, and 24 h in patients receiving tramadol 100 mg than in those receiving tramadol 50 mg or bupivacaine. The mean interval between doses for groups 1, 2 and 3 was 7.40 h, 9.36 h and 5.98 h respectively. The mean interval in group 2 was significantly longer than in group 3 (p < 0.05). The incidence of nausea and vomiting in group 2 was significantly higher than in group 3 (p < 0.05).

Matched MeSH terms: Tramadol/administration & dosage*; Tramadol/adverse effects
Fulltext A comparative study of intravenous patient-controlled analgesia morphine and tramadol in patients undergoing major operation

Hadi MA, Kamaruljan HS, Saedah A, Abdullah NM

Med J Malaysia, 2006 Dec;61(5):570-6.
PMID: 17623958

The success of major surgery depends partly on providing effective post-operative pain relief, which can be commonly achieved by morphine administration via patient- controlled analgesic (PCA) system. Alternatively, tramadol which is a weak opioid analgesic, can be used for post operative pain relief. The purpose of this study was to evaluate the effectiveness of intravenous PCA tramadol in comparison with PCA morphine in term of analgesic properties, sedation and side effects. A randomized, double-blinded study was conducted on 160 ASA I and II patients who underwent major operations. Eighty of them received a loading dose of intravenous morphine 0.1 mg/kg followed by PCA morphine bolus of 1 mg (1 mg/ml) as required, while the other 80 patients received a loading dose of 2.5 mg/kg of intravenous tramadol followed by PCA infusion of 10 mg (10 mg/ml) as required. Patients were monitored for pain, sedation and side effects as well as respiratory rate, nausea, vomiting, pruritus, blood pressure and pulse rate. Patients were evaluated 30 minutes, 4 hours, 24 hours and 48 hours post operation. There were no differences in the demographic data between the two groups (p > 0.05). The overall mean pain score in tramadol group was 0.70 +/- 0.60 as compared to 0.75 +/- 0.67 for morphine group. The mean pain score for tramadol and morphine groups at 30 minutes, 4 hours, 24 hours and 48 hours post operation were 1.32 +/- 0.79, 104 +/- 0.79, 0.35 +/- 0.48, 0.09 +/- 0.33 and 1.35 +/- 0.99, 1.14 +/- 0.81, 0.40 +/- 0.54, 0.10 +/- 0.34 respectively. The overall mean sedation score in tramadol and morphine group was 0.39 +/- 0.44 as compared to 0.35 +/- 0.43 for morphine group. The mean sedation score for tramadol and morphine group at 30 minutes, 4 hours, 24 hours and 48 hours post operation were 0.90 +/- 0.74, 0.56 +/- 0.59, 0.075 +/- 0.27, 0.025 +/- 0.16 and 0.84 +/- 0.70, 0.46 +/- 0.64, 0.08 +/- 0.27, 0.01 +/- 0.11 respectively. There was no significant difference in the overall mean pain and sedation score between the two groups as well as for each duration assessed (p > 0.05). There were also no significant differences between the two groups with regard to the blood pressure and heart rate. The incidence of nausea, vomiting and pruritus were the same in the two groups. This study indicates that PCA tramadol is as equally effective as PCA morphine control following major surgery. The incidences of sedation, nausea or pruritus were the same in the two groups.

Matched MeSH terms: Tramadol/administration & dosage; Tramadol/therapeutic use*
Correlation of tramadol pharmacokinetics and CYP2D6*10 genotype in Malaysian subjects

Gan SH, Ismail R, Wan Adnan WA, Wan Z

J Pharm Biomed Anal, 2002 Sep 05;30(2):189-195.
PMID: 12191703

The aim of the present study is to investigate the influence of the CYP2D6*10 allele on the disposition of tramadol hydrochloride in Malaysian subjects. A single dose of 100 mg tramadol was given intravenously to 30 healthy orthopaedic patients undergoing various elective surgeries. After having obtained written informed consents, patients were genotyped for CYP2D6*10: the most common CYP2D6 allele among Asians by means of allele-specific polymerase chain reaction. The presence of other mutations (CYP2D6*1, *3, *4, *5, *9 and *17) was also investigated. Tramadol was extracted from 1 ml serum with an n-hexane: ethylacetate combination (4:1) after alkalinisation with ammonia (pH 10.6). Serum concentrations were measured by means of high-performance liquid chromatography. The pharmacokinetics of tramadol was studied during the 24 h after the dose. As among other Asians, the allele frequency for CYP2D6*10 among Malaysians was high (0.43). Subjects who were homozygous for CYP2D6*10 had significantly (P=0.046) longer mean serum half-life of tramadol than subjects of the normal or the heterozygous group (Kruskal-Wallis test). When patients were screened for the presence of other alleles, the pharmacokinetic parameter values were better explained. CYP2D6 activity may play a main role in determining tramadol pharmacokinetics. The CYP2D6*10 allele particularly was associated with higher serum levels of tramadol compared with the CYP2D6*1 allele. However, genotyping for CYP2D6*10 alone is not sufficient to explain tramadol disposition.

Matched MeSH terms: Tramadol/blood; Tramadol/pharmacokinetics*
Fulltext Monitoring Consumption of Common Illicit Drugs in Kuala Lumpur, Malaysia, by Wastewater-Cased Epidemiology

Du P, Liu X, Zhong G, Zhou Z, Thomes MW, Lee CW, et al.

Int J Environ Res Public Health, 2020 01 31;17(3).
PMID: 32023897 DOI: 10.3390/ijerph17030889

Southeast Asian countries including Malaysia play a major role in global drug trade and abuse. Use of amphetamine-type stimulants has increased in the past decade in Malaysia. This study aimed to apply wastewater-based epidemiology for the first time in Kuala Lumpur, Malaysia, to estimate the consumption of common illicit drugs in urban population. Influent wastewater samples were collected from two wastewater treatment plants in Kuala Lumpur in the summer of 2017. Concentrations of twenty-four drug biomarkers were analyzed for estimating drug consumption. Fourteen drug residues were detected with concentrations of up to 1640 ng/L. Among the monitored illicit drugs, 3,4-methylenedioxy-methamphetamine (MDMA) or ecstasy had the highest estimated per capita consumptions. Consumption and dose of amphetamine-type stimulants (methamphetamine and MDMA) were both an order of magnitude higher than those of opioids (heroin and codeine, methadone and tramadol). Amphetamine-type stimulants were the most prevalent drugs, replacing opioids in the drug market. The prevalence trend measured by wastewater-based epidemiology data reflected the shift to amphetamine-type stimulants as reported by the Association of Southeast Asian Nations Narcotics Cooperation Center. Most of the undetected drug residues were new psychoactive substances (NPSs), suggesting a low prevalence of NPSs in the drug market.

Matched MeSH terms: Tramadol
Fulltext Subcutaneous administration of tramadol after elective surgery is as effective as intravenous administration in relieving acute pain and inflammation in dogs

Buhari S, Hashim K, Yong Meng G, Mustapha NM, Gan SH

ScientificWorldJournal, 2012;2012:564939.
PMID: 22778699 DOI: 10.1100/2012/564939

Subcutaneous (SC) administration of tramadol was compared with intravenous (IV) administration to evaluate analgesia following canine ovariohysterectomy (OHE). Healthy female dogs (n = 12) between 1 and 3 years of age (1.95 ± 0.65 years), weighing between 10.5 and 17.1 kg (13.12 ± 1.95 kg), were used. Pain was assessed at baseline before surgery and then hourly for 8 hr after surgery. Tramadol was administered both SC and IV at a dose of 3 mg/kg and provided significant postoperative analgesia, as indicated by analgesiometry, β-endorphin levels, and interleukin 6 (IL-6) levels. The respiratory rates and rectal temperatures remained normal and were not significantly different between or within the groups. A significant increase in heart rate was observed at 4 hr for dogs in both groups relative to the baseline, but there was no significant difference in heart rates between the groups at any time point. A significant decrease in mechanical pain threshold was observed within each group after surgery, but both groups responded similarly, suggesting that SC administration of tramadol is as effective as IV administration. Increased serum levels of both IL-6 and β-endorphin 3 hr postoperatively further indicate that both routes of administration achieve similar pain control. Thus, the relative analgesic efficacy of SC tramadol is comparable to that of IV administration and can be used to achieve similar effects for postsurgical pain management in dogs undergoing OHE.

Matched MeSH terms: Tramadol/administration & dosage*
Fulltext An open-label randomised controlled trial on the efficacy of adding intranasal fentanyl to intravenous tramadol in patients with moderate to severe pain following acute musculoskeletal injuries

Chew KS, Shaharudin AH

Singapore Med J, 2017 Oct;58(10):601-605.
PMID: 27193080 DOI: 10.11622/smedj.2016096

INTRODUCTION: The use of intranasal fentanyl as an alternative type of analgesia has been shown to be effective in paediatric populations and prehospital settings. There are a limited number of studies on the use of intranasal fentanyl in adult patients in emergency settings.
METHODS: An open-label study was conducted to evaluate the effectiveness of the addition of 1.5 mcg/kg intranasal fentanyl to 2 mg/kg intravenous tramadol (fentanyl + tramadol arm, n = 10) as compared to the administration of 2 mg/kg intravenous tramadol alone (tramadol-only arm, n = 10) in adult patients with moderate to severe pain due to acute musculoskeletal injuries.
RESULTS: When analysed using the independent t-test, the difference between the mean visual analogue scale scores pre-intervention and ten minutes post-intervention was 29.8 ± 8.4 mm in the fentanyl + tramadol arm and 19.6 ± 9.7 mm in the tramadol-only arm (t[18] = 2.515, p = 0.022, 95% confidence interval 1.68-18.72 mm). A statistically significant, albeit transient, reduction in the ten-minute post-intervention mean arterial pressure was noted in the fentanyl + tramadol arm as compared to the tramadol-only arm (13.35 mmHg vs. 7.65 mmHg; using Mann-Whitney U test with U-value 21.5, p = 0.029, r = 0.48). There was a higher incidence of transient dizziness ten minutes after intervention among the patients in the fentanyl + tramadol arm.
CONCLUSION: Although effective, intranasal fentanyl may not be appropriate for routine use in adult patients, as it could result in a significant reduction in blood pressure.

Matched MeSH terms: Tramadol/administration & dosage*
Fulltext Prescribing of Nonsteroidal Anti-inflammatory Drugs, Tramadol, and Opioids in Children: Patterns of Its Utilization

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: Tramadol
Fulltext Trends and patterns of analgesic prescribing in Malaysian public hospitals from 2010 to 2016: tramadol predominately used

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: Tramadol
Fulltext Tramadol: a valuable treatment for pain in Southeast Asian countries

Vijayan R, Afshan G, Bashir K, Cardosa M, Chadha M, Chaudakshetrin P, et al.

J Pain Res, 2018;11:2567-2575.
PMID: 30425567 DOI: 10.2147/JPR.S162296

Background: The supply of controlled drugs is limited in the Far East, despite the prevalence of health disorders that warrant their prescription. Reasons for this include strict regulatory frameworks, limited financial resources, lack of appropriate training amongst the medical profession and fear of addiction in both general practitioners and the wider population. Consequently, the weak opioid tramadol has become the analgesic most frequently used in the region to treat moderate to severe pain.

Methods: To obtain a clearer picture of the current role and clinical use of tramadol in Southeast Asia, pain specialists from 7 countries in the region were invited to participate in a survey, using a questionnaire to gather information about their individual use and experience of this analgesic.

Results: Fifteen completed questionnaires were returned and the responses analyzed. Tramadol is used to manage acute and chronic pain caused by a wide range of conditions. Almost all the specialists treat moderate cancer pain with tramadol, and every one considers it to be significant or highly significant in the treatment of moderate to severe non-cancer pain. The reasons for choosing tramadol include efficacy, safety and tolerability, ready availability, reasonable cost, multiple formulations and patient compliance. Its safety profile makes tramadol particularly appropriate for use in elderly patients, outpatients, and for long-term treatment. The respondents strongly agreed that tighter regulation of tramadol would reduce its medical availability and adversely affect the quality of pain management. In some countries, there would no longer be any appropriate medication for cancer pain or the long-term treatment of chronic pain.

Conclusions: In Southeast Asia, tramadol plays an important part in the pharmacological management of moderate to severe pain, and may be the only available treatment option. If it were to become a controlled substance, the standard of pain management in the region would decline.

Matched MeSH terms: Tramadol

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