Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ. opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (−)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87–95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%. Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours. The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O-and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.

Clinical Pharmacology of Tramadol

Background
Opioid therapy for chronic noncancer pain (CNCP) is controversial due to concerns regarding long-term effectiveness and safety, particularly the risk of tolerance, dependence, or abuse.

Objectives
To assess safety, efficacy, and effectiveness of opioids taken long-term for CNCP.

Search methods
We searched 10 bibliographic databases up to May 2009.

Selection criteria
We searched for studies that: collected efficacy data on participants after at least 6 months of treatment; were full-text articles; did not include redundant data; were prospective; enrolled at least 10 participants; reported data of participants who had CNCP. Randomized controlled trials (RCTs) and pre-post case-series studies were included.

Data collection and analysis
Two review authors independently extracted safety and effectiveness data and settled discrepancies by consensus. We used random-effects meta-analysis' to summarize data where appropriate, used the I2 statistic to quantify heterogeneity, and, where appropriate, explored heterogeneity using meta-regression. Several sensitivity analyses were performed to test the robustness of the results.

Main results
We reviewed 26 studies with 27 treatment groups that enrolled a total of 4893 participants. Twenty five of the studies were case series or uncontrolled long-term trial continuations, the other was an RCT comparing two opioids. Opioids were administered orally (number of study treatments groups [abbreviated as "k"] = 12, n = 3040), transdermally (k = 5, n = 1628), or intrathecally (k = 10, n = 231). Many participants discontinued due to adverse effects (oral: 22.9% [95% confidence interval (CI): 15.3% to 32.8%]; transdermal: 12.1% [95% CI: 4.9% to 27.0%]; intrathecal: 8.9% [95% CI: 4.0% to 26.1%]); or insufficient pain relief (oral: 10.3% [95% CI: 7.6% to 13.9%]; intrathecal: 7.6% [95% CI: 3.7% to 14.8%]; transdermal: 5.8% [95% CI: 4.2% to 7.9%]). Signs of opioid addiction were reported in 0.27% of participants in the studies that reported that outcome. All three modes of administration were associated with clinically significant reductions in pain, but the amount of pain relief varied among studies. Findings regarding quality of life and functional status were inconclusive due to an insufficient quantity of evidence for oral administration studies and inconclusive statistical findings for transdermal and intrathecal administration studies.

Authors' conclusions
Many patients discontinue long-term opioid therapy (especially oral opioids) due to adverse events or insufficient pain relief; however, weak evidence suggests that patients who are able to continue opioids long-term experience clinically significant pain relief. Whether quality of life or functioning improves is inconclusive. Many minor adverse events (like nausea and headache) occurred, but serious adverse events, including iatrogenic opioid addiction, were rare.

Long‐term opioid management for chronic noncancer pain

Background This review examines the evidence from published data concerning the incidence of moderate-severe and of severe pain after major surgery, with three analgesic techniques; intramuscular (i.m.) analgesia, patient controlled analgesia (PCA), and epidural analgesia. Methods A MEDLINE search of the literature was conducted for publications concerned with the management of postoperative pain. Over 800 original papers and reviews were identified. Of these 212 papers fulfilled the inclusion criteria but only 165 provided usable data on pain intensity and pain relief. Pooled data on pain scores obtained from these studies, which represent the experience of a total of nearly 20 000 patients, form the basis of this review. Results Different pain measurement tools provided comparable data. When considering a mixture of three analgesic techniques, the overall mean (95% Cl) incidence of moderate-severe pain and of severe pain was 29.7 (26.4–33.0)% and 10.9 (8.4–13.4)%, respectively. The overall mean (95% Cl) incidence of poor pain relief and of fair-to-poor pain relief was 3.5 (2.4–4.6)% and 19.4 (16.4–22.3)%, respectively. For i.m. analgesia the incidence of moderate-severe pain was 67.2 (58.1–76.2)% and that of severe pain was 29.1 (18.8–39.4)%. For PCA, the incidence of moderate-severe pain was 35.8 (31.4–40.2)% and that of severe pain was 10.4 (8.0–12.8)%. For epidural analgesia the incidence of moderate-severe pain was 20.9 (17.8–24.0)% and that of severe pain was 7.8 (6.1–9.5)%. The incidence of premature catheter dislodgement was 5.7 (4.0–7.4)%. Over the period 1973–1999 there has been a highly significant (P Conclusions These results suggest that the UK Audit Commission (1997) proposed standards of care might be unachievable using current analgesic techniques. The data may be useful in setting standards of care for Acute Pain Services.

Effectiveness of acute postoperative pain management: I. Evidence from published data

Design. This is a structured evidence-based review of all available studies on the development of abuse/addiction and aberrant drug-related behaviors (ADRBs) in chronic pain patients (CPPs) with nonmalignant pain on exposure to chronic opioid analgesic therapy (COAT).

Objectives.  To determine what percentage of CPPs develop abuse/addiction and/or ADRBs on COAT exposure.

Method.  Computer and manual literature searches yielded 79 references that addressed this area of study. Twelve of the studies were excluded from detailed review based on exclusion criteria important to this area. Sixty-seven studies were reviewed in detail and sorted according to whether they reported percentages of CPPs developing abuse/addiction or developing ADRBs, or percentages diagnosed with alcohol/illicit drug use as determined by urine toxicology. Study characteristics were abstracted into tabular form, and each report was characterized according to the type of study it represented based on the Agency for Health Care Policy and Research Guidelines. Each study was independently evaluated by two raters according to 12 quality criteria and a quality score calculated. Studies were not utilized in the calculations unless their quality score (utilizing both raters) was greater than 65%. Within each of the above study groupings, the total number of CPPs exposed to opioids on COAT treatment was calculated. Similarly, the total number of CPPs in each grouping demonstrating abuse/addiction, ADRBs, or alcohol/illicit drug use was also calculated. Finally, a percentage for each of these behaviors was calculated in each grouping, utilizing the total number of CPPs exposed to opioids in each grouping.

Results.  All 67 reports had quality scores greater than 65%. For the abuse/addiction grouping there were 24 studies with 2,507 CPPs exposed for a calculated abuse/addiction rate of 3.27%. Within this grouping for those studies that had preselected CPPs for COAT exposure for no previous or current history of abuse/addiction, the percentage of abuse/addiction was calculated at 0.19%. For the ADRB grouping, there were 17 studies with 2,466 CPPs exposed and a calculated ADRB rate of 11.5%. Within this grouping for preselected CPPs (as above), the percentage of ADRBs was calculated at 0.59%. In the urine toxicology grouping, there were five studies (15,442 CPPs exposed). Here, 20.4% of the CPPs had no prescribed opioid in urine and/or a nonprescribed opioid in urine. For five studies (1,965 CPPs exposed), illicit drugs were found in 14.5%.

Conclusion.  The results of this evidence-based structured review indicate that COAT exposure will lead to abuse/addiction in a small percentage of CPPs, but a larger percentage will demonstrate ADRBs and illicit drug use. These percentages appear to be much less if CPPs are preselected for the absence of a current or past history of alcohol/illicit drug use or abuse/addiction.

What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review.

For about half a century, the binding of drugs to plasma albumin, the “silent receptor,” has been recognized as one of the major determinants of drug action, distribution, and disposition. In the last decade, the binding of drugs, especially but not exclusively basic entities, to another plasma protein, alpha 1-acid glycoprotein (AAG), has increasingly become important in this regard. The present review points out that hundreds of drugs with diverse structures bind to this glycoprotein. Although plasma concentration of AAG is much lower than that of albumin, AAG can become the major drug binding macromolecule in plasma with significant clinical implications. Also, briefly reviewed are the physiological, pathological, and genetic factors that influence binding, the role of AAG in drug-drug interactions, especially the displacement of drugs and endogenous substances from AAG binding sites, and pharmacokinetic and clinical consequences of such interactions. It can be predicted that in the fulture, rapid auto...

Human alpha-1-glycoprotein and its interactions with drugs

Despite major advances in knowledge and development of efficient techniques for pain control, many patients on surgical wards suffer from modest to severe pain following surgery or trauma. Therefore, in the University Hospital of Kiel, Germany, an anaesthesiology-based acute pain service (APS) was started in 1985 to improve this situation. Organization of an APS. The anaesthesiologist in training who manages the recovery unit serves as an APS for surgical wards and is supervised by a consultant. The anaesthesists on call are responsible after regular working hours. The activities of the APS are as follows: 1. Induction of sufficient postoperative analgesia in the recovery unit for all surgical patients. 2. Clinical rounds on all patients receiving epidural analgesia (EA), other forms of regional analgesia, or patient-controlled analgesia (PCA) every morning and throughout the day if necessary. 3. Additional consultations for postoperative pain management for other patients on request. 4. Assessment and documentation of the clinical status of the patient, quality of analgesia, and side effects. 5. Writing orders for further treatment. 6. Continuing consultations and informal education for ward nurses, physiotherapists, and surgical staff; formal medical training for ward nurses in postoperative pain management. Activity of the APS. From 1985 to 1992, 1947 patients on normal wards were treated (EA: 1736, PCA: 183). Epidural analgesia was performed using a standard protocol with bupivacaine 0.175%-0.25% infused continuously with top-ups if needed (mean 240 mg/day, range 75-600 mg; median duration 7 days, range 1-53, Table 1). Demand for further treatment was proved by day-to-day withdrawal. Since the introduction of an APS, complications of EA such as hypotension (1985/1986:5.1%; 1987/1992:0.5%, Table 3) and insufficient analgesia due to dislocation or other technical complications could be reduced significantly (Table 3). Dermal infections were seen in 2.6% of patients, with a significantly higher incidence in patients with arteriosclerotic diseases (4.1%). Epidural opioids were used in only 46 selected cases on surgical wards. Nevertheless, 2 cases of marked respiratory depression occurred. The overall risk of complications during postoperative EA could be reduced from 1:11 cases in the first 2 years to 1:20 in the last 6 years since introducing the APS. For other regional procedures (e.g., interpleural analgesia) no complications were recorded. PCA was performed using a standard protocol with tramadol or piritramide without background infusion (Table 6). The loading dose was titrated in the recovery unit.(ABSTRACT TRUNCATED AT 400 WORDS)

[Postoperative pain therapy at general nursing stations. An analysis of eight year's experience at an anesthesiological acute pain service].

The term "sympathetically maintained pain" (SMP) describes a symptom that might accompany a variety of diseases (CRPS, (post-) herpetic and post-injury neuralgia), which might transform into sympathetically independent pain (SIP) after some time. Patients with SMP present a bunch of disorders of the autonomic and sensory system, but the only reliable way to diagnose a pain as SMP is a positive response to an intervention at the sympathetic nervous system. Three ways of influencing the sympathetic system are commonly used: (a) local anesthetic sympathetic blockade (SB), (b) intravenous regional sympathectomy (IVRS) and (c) ganglionic local opioid application (GLOA). A review of current literature shows that SB has certain advantages in diagnostic sensitivity, whereas GLOA might be slightly superior in therapy of some diseases with longstanding pain history. Obviously, the therapeutic benefit of all interventions is complete independent of the accompanying autonomic disorder and of a blockade of efferent fibers. A new heuristic model of the SMP mechanism is presented, including both experimental and clinical data. For reducing the risks of false positive or negative diagnosis of SMP and SIP, a diagnostic algorithm is proposed. This includes optimizing the technique, changes of interventional measures, and adequate monitoring both of analgesia and as well of the extend of efferent sympathetic blockade (e.g. measurement of sympathetic reflexes). The treatment recommendations in patients with SMP vary in dependence of the kind of disease. In SMP, invasive measures play an important, but only limited role within the comprehensive treatment concept. As an example a three-stage, symptom-adapted treatment algorithm is demonstrated for CRPS, including also drug therapy, psychologic and physiotherapeutic approaches.

Diagnostic and treatment measures in patients with sympathetically maintained pain

We describe a method, which is both specific and rapid, for the measurement of bupivacaine concentrations in plasma using high-performance liquid chromatography. Bupivacaine plasma concentrations, pharmacokinetics and protein binding in the postoperative period were investigated in seven patients (58–77 years old) following hip surgery. Postoperative analgesia was achieved by epidural bolus injections of 25 mg bupivacaine 0.25% every 6 h. Sufficient pain relief without side-effects was obtained. Total (maximum 1.13 μg/ml) as well as free (maximum 0.1 μg/ml) bupivacaine plasma concentrations remained below toxic threshold levels and no cumulation occurred. Increased protein binding in the postoperative period is reported, emphasizing the importance of measuring the free fraction in addition to the total plasma concentration. The free fraction decreased from 5.4% preoperatively to 2.7% in the postoperative period (P<0.05). Changes in plasma protein binding of bupivacaine and changes in plasma levels of the acute phase reactant α-1-acid glycoprotein were correlated (r = 0.8, P<0.05). Difficulties in interpreting the elimination parameters following epidural administration are discussed, leading to the conclusion that the derivation of dosage regimens from kinetic parameters following epidural administration is not warranted.

Pharmacokinetics and protein binding of bupivacaine in postoperative epidural analgesia

In a prospective study 60 patients receiving morphine for treatment of mostly neuropathic and musculoskeletal pain of non-malignant origin were investigated. The aim of the study was to determine the characteristics of responders to morphine therapy and the frequency and severity of side effects. METHODS. Eligible patients suffered from chronic pain that had not been relieved despite all current therapy. All of them received controlled-release morphine tablets. Dose was increased in case of insufficient pain relief. Before morphine treatment and at the follow-ups pain intensity was rated on a numeric analogous scale, analgesia and side effects on a four-stage verbal rating scale. Intake of the prescribed and other drugs was randomly controlled by urine analysis. The patients were divided in three groups retrospectively: group I, non-responders who ceased the morphine therapy within 1 month due to weak analgesia or severe side effects; group II, patients in whom the therapy was stopped within the following months despite persisting pain; group III, patients who continued therapy. STATISTICS. ANOVA, chi-squared test, non-parametric tests (Kruskal-Wallis, Wilcoxon). Results were accepted as significant at p < 0.05. RESULTS. Twenty-three patients were non-responders. Fourteen other patients stopped the therapy after initial response because the side effects exceeded the benefit of analgesia (group II). Only 10 of the remaining 23 responders had good analgesia and minor side effects during the observation time. Constipation, despite prophylactic laxatives, and nausea were the most frequently reported events causing cessation of therapy. Analgesia and side effects in groups II and III were constant during the observation time of 241 (36-1486) days. In groups II and III, 43% of the patients needed an increase of the morphine dosage during therapy. The initially sufficient morphine dosage was significantly higher in group II than in group III; only one patient needed more than 90 mg/day in group III. Urine screening tests in 45 patients disclosed that 18 patients concealed the intake of other opioids or psychotropic drugs, mostly benzodiazepines. CONCLUSIONS. The study showed many problems with the patients' compliance and acceptance of oral morphine due to side effects and lack of analgesia. The discrepancy from other, positive reports might be explained by the extremely selected patients of this study and by the fact that not only responders were included for evaluation. Patients' compliance seems to have been overestimated in previous studies because no urinary controls were taken.

[Morphine tablets for chronic non-tumor-induced pain. Which factors modify the success or failure of a long-term therapy?].

Background: In a retrospective analysis of intraoperative somatosensory evoked potential (SEP) results during carotid artery surgery we found some cases with postoperative neurologic deficits, surprisingly without significant SEP changes.



Methods: Median nerve SEP were monitored as usual. Indication for selective shunting was a complete loss of amplitude N20/P25 in the first period of the investigation, later on a 50% reduction, or a prolongation of the central conduction time (CCT) of about 1.5 ms after cross-clamping. Anaesthesia was maintained with isoflurane in N2O/O2, fentanyl and atracurium.



Results: Over a 3-year period 146 patients were monitored. Indications were: transient ischaemic attacks (TIA) (n=51), stroke (n=23), stroke with residuals (n=39), asymptomatical stenosis (n=29), subclavian steal syndrome (n=4). Twenty-four patients received an intraluminal shunt following SEP alterations. Post-operatively, 5 patients (3.4%) had symptoms of intraoperative brain ischaemia (stroke n=2, TIA n=3), 4 of them showing only minor intraoperative SEP alterations; 1 received a shunt because of CCT prolongation. Four of these 5 patients had cerebral neurologic deficiency preoperatively.



Conclusion: Since some authors have found a 100% sensitivity of intraoperative SEP, it is remarkable, that 1 patient with postoperative stroke and 3 patients with TIA had no significant SEP changes intraoperatively. We suppose there was an association with preoperative neurological deficits resulting from previous strokes. In such cases, regional critical ischaemia may apparently occur outside the sensory pathway monitored with SEP.

Intraoperative monitoring with somatosensory evoked potentials in carotid artery surgery--less reliable in patients with preoperative neurologic deficiency?

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

C. Maier

Author Tools

Chat about Author